griseofulvin and Porphyrias

An important factor in disruption of hepatic heme biosynthesis by porphyrinogenic drugs appears to be interaction with one or several cytochrome P450 isozymes. Clarification of the nature of the interaction between porphyrinogenic drugs and cytochrome P450 isozymes, as well as identification of the isozymes involved, will be helpful in extrapolating the results of animal experimentation to humans. Administration of griseofulvin to mice results in accumulation in the liver of two N-alkylated protoporphyrins (PPs). The major N-alkyl PP, N-griseofulvin PP, which is devoid of ferrochelatase-inhibitory activity, was shown to be the precursor of N-methyl PP, which is a potent ferrochelatase inhibitor. N-Griseofulvin PP was present predominantly as the Nc regioisomer rather than the anticipated NA regioisomer. Progesterone (PG) 6 beta-hydroxylase and androstenedione (AD) 6 beta-hydroxylase, diagnostic markers for cytochrome P450 3A1/2 activity in rat liver, were identified in chick embryo liver. The in ovo administration of 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine (4-ethyl DDC) and 3-[2-(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone (TTMS) caused inactivation of chick embryo hepatic PG and AD 6 beta-hydroxylases. Ascorbate was shown to inhibit uroporphyrin accumulation in cultures of chick embryos treated with porphyrinogenic drugs and in the livers of an ascorbate-requiring rat strain treated with a porphyrinogenic combination of chemicals. Ascorbate appears to act by inhibiting oxidation of uroporphyrinogen to uroporphyrin. Avian hepatocytes were cultured in 48-well plates and directly assayed within the wells for the activity of 7-ethoxyresorufin O-deethylation (EROD), and for porphyrin and protein concentration by a fluorescence plate reader. Uroporphyrin was the main porphyrin to accumulate in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in chick embryos, pheasants, ducks, and herring gulls; heptacarboxylated porphyrin predominated in turkey hepatocytes. The EROD-inducing potential of complex mixtures of polyhalogenated aromatic hydrocarbons from herring gull eggs was assessed and compared with that of TCDD. A nuclear heme pool appears to regulate the transcription of the cytochrome P450 2B1/2B2 genes in rat liver, by modulating binding of a transcription factor(s) that appears to be involved in the transcriptional activation by phenobarbitone.

Topics: Animals; Cytochrome P-450 Enzyme System; Griseofulvin; Heme; Liver; Mice; Porphyrias; Rats

There are many chemicals that affect porphyrin metabolism. Certain of these can be used to induce experimental porphyria in animal. Human porphyrias are relatively uncommon, thus preventing their adequate examination in human patients. But using experimental animals, the pathogenesis, biochemical pathways and treatment of these diseases may be studied. In this paper, we conducted our own investigations on griseofulvin induced protoporphyria, and also reviewed experimental porphyrias induced by hexachlorobenzen and polychlorinated biphenyls.

Topics: Animals; Disease Models, Animal; Griseofulvin; Hexachlorobenzene; Humans; Mice; Polychlorinated Biphenyls; Porphyrias

Topics: 5-Aminolevulinate Synthetase; Animals; Animals, Newborn; Cycloheximide; Cytochrome P-450 Enzyme System; Dicarbethoxydihydrocollidine; Enzyme Induction; Griseofulvin; Heme; Liver; Microsomes, Liver; Pharmacology; Phenylbutazone; Porphyrias; Porphyrins; Proadifen; Protein Biosynthesis

Topics: Aging; Animals; Child; Chloral Hydrate; Dogs; Drug Antagonism; Drug Resistance, Microbial; Endoplasmic Reticulum; Enzyme Induction; Female; Genetics, Microbial; Griseofulvin; Humans; Hypnotics and Sedatives; Infant, Newborn; Insecticides; Lupus Erythematosus, Systemic; Male; Mice; Microscopy, Electron; Microsomes; Molecular Biology; Penicillinase; Phenobarbital; Porphyrias; Rabbits; Rats; Steroids; Warfarin

Topics: Animals; Chlorpropamide; Drug-Related Side Effects and Adverse Reactions; Estrogens; Griseofulvin; Humans; Hypnotics and Sedatives; Liver; Mice; Phenobarbital; Porphyrias; Porphyrins; Rats; Sulfones; Tolbutamide

It has been demonstrated that the function of mammalian clock gene transcripts is controlled by the binding of heme in vitro. To examine the effects of heme on biological rhythms in vivo, we measured locomotor activity (LA) and core body temperature (T(b)) in a mouse model of porphyria with impaired heme biosynthesis by feeding mice a griseofulvin (GF)-containing diet. Mice fed with a 2.0% GF-containing diet (GF2.0) transiently exhibited phase advance or phase advance-like phenomenon by 1-3 h in terms of the biological rhythms of T(b) or LA, respectively (both, P < 0.05) while mice were kept under conditions of a light/dark cycle (12 h:12 h). We also observed a transient, ~0.3 h shortening of the period of circadian T(b) rhythms in mice kept under conditions of constant darkness (P < 0.01). Interestingly, the observed duration of abnormal circadian rhythms in GF2.0 mice lasted between 1 and 3 wk after the onset of GF ingestion; this finding correlated well with the extent of impairment of heme biosynthesis. When we examined the effects of therapeutic agents for acute porphyria, heme, and hypertonic glucose on the pathological status of GF2.0 mice, it was found that the intraperitoneal administration of heme (10 mg·kg(-1)·day(-1)) or glucose (9 g·kg(-1)·day(-1)) for 7 days partially reversed (50%) increases in urinary δ-aminolevulinic acids levels associated with acute porphyria. Treatment with heme, but not with glucose, suppressed the phase advance (-like phenomenon) in the diurnal rhythms (P < 0.05) and restored the decrease of heme (P < 0.01) in GF2.0 mice. These results suggest that impairments of heme biosynthesis, in particular a decrease in heme, may affect phase and period of circadian rhythms in animals.

Topics: Animals; Body Temperature; Circadian Rhythm; Disease Models, Animal; Glucose; Griseofulvin; Heme; Locomotion; Male; Mice; Mice, Inbred ICR; Porphyrias

In central nervous system, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) hydrolyse acetylcholine. Diminished cholinesterase activity is known to alter several mental and psychomotor functions. The symptoms of cholinergic crisis and those observed during acute attacks of acute intermittent porphyria are very similar. The aim of this study was to investigate if there could be a link between the action of some porphyrinogenic drugs on brain and the alteration of the cholinergic system. To this end, AChE and BuChE activities were assayed in whole and different brain areas. Muscarinic acetylcholine receptor (mAChR) levels were also measured. Results obtained indicate that the porphyrinogenic drugs tested affect central cholinergic transmission. Quantification of mAChR gave quite different levels depending on the xenobiotic. Veronal administration inhibited 50% BuChE activity in whole brain, cortex and hippocampus; concomitantly cortex mAChR was 30% reduced. Acute and chronic isoflurane anaesthesia diminished BuChE activity by 70-90% in whole brain instead cerebellum and hippocampus mAChR levels were only altered by chronic enflurane anaesthesia. Differential inhibition of cholinesterases in the brain regions and their consequent effects may be of importance to the knowledge of the mechanisms of neurotoxicity of porphyrinogenic drugs.

Topics: 5-Aminolevulinate Synthetase; Acetylcholinesterase; Animals; Barbital; Brain; Butyrylcholinesterase; Cholinesterases; Enflurane; Ethanol; Griseofulvin; Male; Mice; Nervous System Diseases; Porphyrias; Receptors, Muscarinic; Starvation

Several porphyrinogenic xenobiotics cause mechanism-based inactivation of cytochrome P450 (P450) isozymes with concomitant formation of a mixture of four N-alkylprotoporphyrin IX (N-alkylPP) regioisomers, which have ferrochelatase inhibitory properties. To isolate the four regioisomers of N-methylprotoporphyrin IX (N-methylPP), 3,5-diethoxycarbonyl, 1-4-dihydro-2,4,6-trimethylpyridine (DDC) was administered to untreated, beta-naphthoflavone-, phenobarbital-, and glutethimide-pretreated 18-day-old chick embryos. Separation of the N-methylPP regioisomers by high pressure liquid chromatography (HPLC) revealed no marked difference in the regioisomer pattern among the different treatments. After administration of griseofulvin, allylisopropylacetamide (AIA), or 1-[4-(3-acetyl-2,4,6-triemethylphenyl)-2,6-cyclohexanedionyl]-O-ethyl propionaldehyde oxime (ATMP) to untreated and glutethimide-pretreated 18-day-old chick embryos, an N-alkylPP was isolated after AIA administration only. This finding strengthened previous reports of the species specificity of N-alkylPP formation with griseofulvin and ATMP. A series of dihydropyridines, namely 4-ethylDDC, 4-hexylDDC, and 4-isobutylDDC were administered to untreated and glutethimide-pretreated 18-day-old chick embryos and hepatic N-alkylPPs were isolated and separated by HPLC into regioisomers. The regioisomer patterns obtained did not support a previous proposal of masked regions above both rings B and C in the heme moieties of the P450 isozymes responsible for N-alkylPP formation. However, the data support the hypothesis of a partially masked region above ring B alone. The regioisomer patterns were in agreement with results previously obtained in rats showing that the percentage of Nc and (or) ND regioisomers in the regioisomer mixture increases as the length and bulk of the 4-alkyl substituent of a DDC analogue increase. Differences in the regioselectivity of heme N-alkylation may be due to intrinsic chemical features of DDC analogues themselves or to differences in the P450 isozymes inactivated.

Topics: Animals; Chick Embryo; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; Glutethimide; Griseofulvin; Isoenzymes; Liver; Molecular Structure; Porphyrias; Porphyrins; Protoporphyrins; Stereoisomerism; Xenobiotics

The results of our previous studies demonstrated that isonicotinic acid hydrazide (INH) can aggravate griseofulvin (GF)-induced protoporphyria in mice. To elucidate this phenomenon, we studied the relationship between liver protoporphyrin (PP) levels and N-acetyltransferase (NAT) activity, which is known to be a major catabolic enzyme of INH metabolism in the liver. The results revealed a significant correlation between liver PP levels and NAT activity in the mice fed 0.1% GF and 0.05% INH. In this group, mice with high NAT activity developed severe protoporphyria. There was no correlation, however, between liver PP levels and NAT activity in the mice fed GF alone or INH alone. The result suggested that INH metabolites formed by NAT enhance the hepatotoxicity of GF in mice.

Topics: Animals; Arylamine N-Acetyltransferase; Drug Synergism; Griseofulvin; Isoniazid; Liver; Male; Mice; Mice, Inbred Strains; Porphyrias; Protoporphyrins

To investigate the hepatic abnormalities accompanying experimental protoporphyria due to griseofulvin (GF), liver function test values and porphyrin levels in mice were assayed at days 2, 4, 8, and 16 after starting the administration of 0.5% GF feed. Furthermore, in an attempt to elucidate the harmful effects of GF on liver functions, the above mentioned assay was also performed after the feed was discontinued in mice given 0.5% GF feed for 16 days. The hepatic protoporphyrin (PP) level had already risen by day 2, but the erythrocytic PP level was within normal limits at that time. Hepatic PP levels increased gradually, followed by an increase in erythrocytic PP levels. The variation in liver function test values roughly paralleled the porphyrin levels. Over the time span of the response to GF, the variations in the serum glutamate oxaloacetate transaminase (S-GOT) levels, serum glutamate pyruvate transaminase (S-GPT) levels, and leucine amino peptidase (LAP) levels resembled those in hepatic PP. On the other hand, the changes in alkaline phosphatase (ALP) levels paralleled those of the erythrocytic PP levels. Erythrocytic and fecal protoporphyrin levels decreased to the normal level one month after the discontinuation of GF administration, but the hepatic protoporphyrin level still was 53.6 times higher than the normal level two months after switching to normal feed. The values of liver function tests had returned to within the normal range after one month. By the fourth day after the administration of GF, a brown pigmented material could be observed around the hepatocytes and the Glisson sheath; the amount of this material increased day by day.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Erythrocytes; Feces; Griseofulvin; Liver; Liver Function Tests; Male; Mice; Mice, Inbred Strains; Porphyrias; Protoporphyrins

The ability of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), 3,5-diethoxycarbonyl-4-ethyl-1,4-dihydro-2,6-dimethylpyridine (EDDC) and griseofulvin to induce porphyria in primary cultures of mouse hepatocytes has been examined. Exposure of cultured mouse hepatocytes to DDC, EDDC or griseofulvin resulted in a marked inhibition of ferrochelatase which was sustained over the 4-day exposure period. Maximal concentrations of DDC (25 microM), EDDC (25 microM) and griseofulvin (25 microM) resulted in 14-fold, 30-fold and 9-fold increases, respectively, in total porphyrin in the culture medium. Analysis of the porphyrins accumulating indicated a predominance of protoporphyrin with all three xenobiotics. Addition of 5-aminolaevulinic acid (ALA) to mouse hepatocyte cultures (10-1000 microM) resulted in much larger increases (up to 164-fold) in porphyrin accumulation in the medium and the porphyrin accumulating was predominantly uroporphyrin. These studies have demonstrated that primary cultures of mouse hepatocytes provide a valid mechanism-based in vitro model of the hepatic porphyrias produced by the dihydropyridines and griseofulvin in mice.

Topics: Aminolevulinic Acid; Animals; Cells, Cultured; Chemical and Drug Induced Liver Injury; Dicarbethoxydihydrocollidine; Ferrochelatase; Griseofulvin; Liver; Liver Diseases; Male; Mice; Porphyrias; Porphyrins

Griseofulvin(GF) has become the drug of choice as an antifungal agent for patients who suffer from many kinds of fungal infection. In order to clarify hepatic injury by griseofulvin(GF) overload and the effect of UDCA on GF-induced hepatic injury, the authors carried out biochemical, histologic, and ultrastructural studies of liver following treatment with griseofulvin and ursodeoxycholic acid(UDCA) in mice. Urine porphobilinogen excretion in the group treated with GF alone was significantly increased and reached the highest level in the 4th week and declined thereafter. Biochemical studies of the liver function showed no remarkable changes of serum bilirubin levels throughout the experimental period in all groups, except for SGPT and alkaline phosphatase activities which were significantly elevated and reached the highest level in the second week. Then they slightly decreased in GF treated groups(GF alone and GF plus UDCA) in comparison with the control group. Pathologic findings in the group treated with GF alone include focal liver cell necrosis(esp, zone 3), Mallory bodies in hepatocytes(esp, zone 1), Kupffer cell activation, and brown protoporphyrin pigments in the hepatocytes, bile canaliculi and interlobular bile ducts with a marked inflammatory cell infiltration in the portal tracts. Under the polarizing light microscope, bile ductular and canalicular thrombi showed a "Maltese cross" birefringence in mice treated with GF alone. There is no definite finding of fatty change in hepatocyte. Under the microscope, the liver appeared normal with an intact lobular architecture in the GF plus UDCA treated group. Electron microscopically, GF-induced changes include swelling of mitochondria, globular protoporphyrin crystals in the hepatocyte cytoplasm, markedly dilated bile cannaliculi and bile ducts and the formation of a Mallory hyaline bodies in the hepatocytes. There were no noticeable structural changes in the GF plus UDCA-treated group. Therefore the results suggest that GF causes hepatic injury, namely porphyria and cholestasis, and the treatment of UDCA may have cytoprotective and choleretic effects on GF-induced hepatic injuries.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Bilirubin; Chemical and Drug Induced Liver Injury; Griseofulvin; Liver Diseases; Mice; Mice, Inbred ICR; Microscopy, Electron; Porphobilinogen; Porphyrias; Ursodeoxycholic Acid

1. We have compared the response to griseofulvin of rats and mice and, in mice, the effect of griseofulvin itself with that of two of its analogues. The severity of protoporphyria shows a correlation with the accumulation of both types of N-alkylated porphyrins previously described after treatment with this drug, namely N-methylproptoporphyrin and the N-griseofulvin protoporphyrin adduct. 2. Both N-alkylporphyrins are chiral, are labelled from 5-amino[4-14C]laevulinate, and their liver accumulation can be inhibited by pretreatment with a suicide substrate of cytochrome P-450, which also prevents porphyria. 3. These findings suggest that cytochrome P-450 is involved in the mechanism of griseofulvin-induced protoporphyria by generating N-methylprotoporphyrin. The N-griseofulvin protoporphyrin adduct may also originate from cytochrome P-450, but more work is necessary to elucidate whether it acts as the precursor for N-methylprotoporphyrin.

Topics: Animals; Cytochrome P-450 Enzyme System; Griseofulvin; Humans; Infant, Newborn; Male; Mice; Porphyrias; Protoporphyrins; Rats

To investigate the influence of ursodesoxycholic acid (URSO) on griseofulvin (GF)-induced protoporphyria mice, analysis of hepatic, erythrocytic, and fecal porphyrin levels and histopathological examinations were performed in dd-Y strain mice treated with 0.5% GF and/or 0.5% URSO. We observed no difference of hepatic and fecal porphyrin levels between the GF group and GF with URSO group, although an elevation of erythrocytic porphyrin levels was seen in the GF with URSO group. However, remarkable hepatic atrophy revealed in the GF with URSO group. Furthermore, a strong emission of red fluorescence was observed in the liver under long wave ultraviolet. Histopathologically, many focal necrosis was found in the liver specimen treated with GF and URSO. We expected that URSO might facilitate the excretion of porphyrin from bile to feces because of suppression of transfer from serum to erythrocyte like cholic acid (CA). But, the action of URSO appears to be different from that of CA. We consider that the 0.5% concentration of URSO plays a role in the cytotoxic effect to the liver.

Topics: Animals; Chemical and Drug Induced Liver Injury; Griseofulvin; Liver Diseases; Male; Mice; Mice, Inbred Strains; Porphyrias; Protoporphyrins; Ursodeoxycholic Acid

Abnormal porphyrin metabolism can be induced by several chemicals. To investigate the synergistic effect on porphyrinopathy of isonicotinic acid hydrazide (INH) with a low concentration of griseofulvin (GF), the two chemicals were given to mice simultaneously. INH was added to drinking water at a concentration of 0.05%. GF was mixed with feed at a concentration of 0.1%. The mice (dd-y strain) were divided into four groups. Those in group A were fed normally. Group B received only 0.1% GF, group C received only 0.05% INH, and group D received both 0.1% GF and 0.05% INH. The treatment was continued for 13 to 30 weeks. After treatment, the mice were anesthetized and sacrificed. The liver and whole blood were taken for analysis of porphyrins. The results revealed a slight elevation of erythrocytic porphyrins in the groups treated with 0.1% GF or 0.05% INH alone and remarkable abnormalities in the hepatic and erythrocytic porphyrin levels of the group simultaneously treated with both chemicals. These results show that INH itself may have a small potential for the induction of porphyric abnormalities, and that the administration of INH with a low concentration of GF induces marked porphyrinopathy in dd-y strain mice.

Topics: Animals; Drug Synergism; Drug Therapy, Combination; Griseofulvin; Isoniazid; Liver; Mice; Porphyrias; Porphyrins

A hepatic green pigment, inhibitory toward ferrochelatase, has been isolated from the liver of mice treated with griseofulvin, isogriseofulvin, or 3,5-diethoxycarbonyl-1,4-dihydrocollidine and has been shown to exhibit identical chromatographic characteristics to authentic N-methyl protoporphyrin. All four possible structural isomers have been demonstrated, and each drug produced primarily the same isomer. N-Methyl protoporphyrin has also been found in very small amounts in the liver of untreated mice, but the isomeric composition appeared to differ from that of the drug-induced N-methyl protoporphyrin. Intraperitoneal administration of 3,5-diethoxy-carbonyl-1,4-dihydrocollidine to female C3H/He/Ola and NIH/Ola inbred mice produced a marked dose-related loss of hepatic ferrochelatase activity, which was identical in magnitude in the two strains. Induction of hepatic 5-aminolevulinate synthase (ALA-S), and accumulation of liver protoporphyrin, however, were greater in C3H/He/Ola mice. The strain difference in ALA-S response was most marked when inhibition of ferrochelatase (the "specific" effect of the drug) was maximal, and this suggests that a genetic variation exists in the sensitivity of ALA-S to a second drug action, the so-called nonspecific action, which is shared by many lipid-soluble compounds. Male mice of three strains accumulated greater amounts of hepatic protoporphyrin than females after treatment with griseofulvin, yet no significant difference was found between the two sexes in the extent of ferrochelatase inhibition. Stimulation of ALA-S activity was slightly greater in males, but when porphyria was very marked, ALA-S activities were significantly lower in this sex.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Chromatography, High Pressure Liquid; Dicarbethoxydihydrocollidine; Female; Ferrochelatase; Griseofulvin; Isomerism; Liver; Male; Mice; Mice, Inbred C3H; Mice, Inbred Strains; Porphyrias; Porphyrins; Protoporphyrins; Sex Factors; Species Specificity

In nude mice grieofulvin given by intraperitoneal injections produces a severe porphyric state within 1 week. Compared with peroral administration of griseofulvin to produce experimental porphyria, this model is much more efficient and can be more easily controlled.

Topics: Animals; Chemical and Drug Induced Liver Injury; Chromatography, Liquid; Disease Models, Animal; Erythropoiesis; Griseofulvin; Injections, Intraperitoneal; Male; Mice; Mice, Nude; Porphyrias; Porphyrins; Protoporphyrins; Skin Diseases

Some reports link human hepatic porphyria with a risk of hepatocellular carcinoma. Hepatic protoporphyria and uroporphyria were induced in mice by feeding griseofulvin and hexachlorobenzene (HCB), respectively. These chemicals also cause liver cancer. Hepatic immunoreactive cytosolic levels of heme-binding Z protein (HBP) were reduced by 81% (griseofulvin) and 55% (HCB). In contrast, both treatments caused a greater than 4-fold increase in the immunoreactive levels of glutathione S-transferase isozymes (GST) which like HBP also bind heme. Unlike in vitro studies in the presence of porphyrins, no cross-linking of HBP was observed in vivo.

Topics: Animals; Blotting, Western; Carcinogens; Carrier Proteins; Chlorobenzenes; Cross-Linking Reagents; Electrophoresis, Polyacrylamide Gel; Griseofulvin; Heme; Heme-Binding Proteins; Hemeproteins; Hexachlorobenzene; Liver; Male; Mice; Mice, Inbred BALB C; Molecular Weight; Porphyrias

Topics: Administration, Oral; Animals; Cholic Acid; Cholic Acids; Griseofulvin; Mice; Mice, Inbred Strains; Porphyrias; Porphyrins; Protoporphyrins

Topics: Animals; Griseofulvin; Liver; Mice; Mice, Hairless; Porphyrias; Porphyrins; Skin; Skin Diseases; Species Specificity

Topics: Animals; Chemical and Drug Induced Liver Injury; Griseofulvin; Liver; Liver Diseases; Mice; Porphobilinogen Synthase; Porphyrias

Topics: Animals; Erythrocytes; Griseofulvin; Liver; Porphyrias; Protoporphyrins; Species Specificity

Topics: Animals; Chemical and Drug Induced Liver Injury; Griseofulvin; Liver; Liver Diseases; Male; Mice; Porphyrias; Porphyrins; Protoporphyrins

The content of iron and protoporphyrin in liver mitochondria from mice with porphyria induced by griseofulvin was measured. The amount of porphyrin was 0.0076 +/- 0.0043, 4.11 +/- 0.58 and 22.2 +/- 6.8 nmol/mg protein (n = 5) in mitochondria from control animals and animals treated with griseofulvin for 3 days and 4-5 weeks, respectively. The energy coupling of the mitochondria was greatly diminished after 4-5 weeks of treatment, and the ferrochelatase activity was inhibited 80-90%, compared to that of control animals. Mitochondrial preparations isolated by differential centrifugation were contaminated with iron-containing lysosomes which could be removed by Percoll density-gradient centrifugation. In purified mitochondrial preparations no change in the amount of non-heme iron was found after griseofulvin feeding, representing 3.36 +/- 0.15, 3.97 +/- 0.40 and 3.59 +/- 0.23 nmol/mg protein for control animals, 3 days- and 4-5 weeks-treated animals, respectively (n = 4). A mitochondrial iron pool previously identified in rat liver mitochondria and shown to be available for heme synthesis in vitro (Tangerås, A. (1985) Biochim. Biophys. Acta 843, 199-207) was also present in mitochondria from mice. The magnitude of this iron pool, as well as its availability for heme synthesis, was not changed after treatment of the animals with griseofulvin. The fact that porphyrin, but not iron, accumulated in the mitochondria when ferrochelatase was inhibited is discussed with regard to our understanding of the process of heme synthesis and its regulation.

Topics: Animals; Chemical and Drug Induced Liver Injury; Griseofulvin; Heme; Iron; Liver Diseases; Lyases; Mice; Mitochondria, Liver; Oxidative Phosphorylation; Oxygen Consumption; Porphyrias; Porphyrins; Protoporphyria, Erythropoietic

Topics: Animals; Griseofulvin; Humans; Mice; Mice, Inbred Strains; Porphyrias; Porphyrinogens

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Griseofulvin; Liver; Mice; Porphyrias; Porphyrins

Topics: Animals; beta Carotene; Canthaxanthin; Carotenoids; Dicarbethoxydihydrocollidine; Griseofulvin; Light; Mice; Mice, Nude; Porphyrias; Skin; Skin Diseases

Short-term effects of cholic acid ingestion on hepatic accumulation, fecal excretion, and blood levels of protoporphyrin were studied in vivo in griseofulvin-induced protoporphyric mice. Experimental mice that received feed with 2% griseofulvin and 0.5% cholic acid were compared with control mice that received feed with 2% griseofulvin for 4 wk. Five mice from each group were assessed each week for liver and blood porphyrin levels. Fecal protoporphyrin was compared weekly in the total pooled output of each population. Mean protoporphyrin levels were significantly lower for liver (P less than 0.0001), erythrocytes (P less than 0.05), and plasma (P less than 0.05), and higher for feces (P less than 0.001) for the mice that were fed cholic acid. Microscopic protoporphyrin deposits, inflammation, necrosis, and dysplasia were more severe in livers of control mice. A second experimental design compared four regimens in the feed given to all mice after 1-wk induction with 2% griseofulvin: (a) 0.5% cholic acid, (b) no adulterant, (c) 2% griseofulvin and 0.5% cholic acid, and (d) 2% griseofulvin. No difference in protoporphyrin removal from livers of mice in groups 1 and 2 was observed after 1 and 2 wk of these regimens. The apparent reduction in hepatic protoporphyrin content in mice of group 3 as compared with group 4 at weeks 2 and 3 was not significant at P less than 0.05. These data suggest that in selected circumstances, hepatic protoporphyrin secretion may be enhanced in protoporphyric disease states by bile salt supplementation.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cholic Acids; Disease Models, Animal; Feces; Female; Griseofulvin; Humans; Liver; Liver Diseases; Mice; Porphyrias; Porphyrins; Protoporphyrins

Administration of 2.5% griseofulvin in the diet to male CD1 mice produced protoporphyria and cholestasis. Protoporphyria became evident as early as after 10 days of treatment, whereas cholestasis, expressed in terms of total bile flow reduction, developed only after 45 days of griseofulvin. Bile flow impairment was due both to the length of treatment and to the severity of liver protoporphyria. Griseofulvin administration was also associated with a significant modification of the relative amounts of hepatic microsomal cytochromes P-450 and b5, a loss in concentration/mg of protein of cytochrome P-450 and a concomitant increase of b5. Despite these changes, the activity of aniline hydroxylase expressed per mg of microsomal protein, assessed in vitro, was not modified.

Topics: Aniline Hydroxylase; Animals; Bile; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Cholestasis; Cytochrome b Group; Cytochrome P-450 Enzyme System; Cytochromes b5; Griseofulvin; Lipid Metabolism; Liver Diseases; Male; Mice; Microsomes, Liver; Mixed Function Oxygenases; Porphyrias; Porphyrins; Protoporphyrins

Numerous drugs and environmental chemicals are capable of influencing the clinical expression of human hepatic porphyria primarily by interfering with the orderly regulation of heme synthesis in the liver. Some agents trigger the disease in otherwise normal individuals whereas others exacerbate an underlying genetic abnormality leading to disease expression. In both instances careful avoidance of exposure to these drugs and chemicals can largely prevent the development of manifest disease. The mechanisms whereby these agents impair the normal regulation of hepatic heme synthesis have been carefully studied in recent years and have provided valuable new insights into this form of drug-induced hepatotoxicity.

Topics: 5-Aminolevulinate Synthetase; Allyl Compounds; Aminolevulinic Acid; Barbiturates; Chemical and Drug Induced Liver Injury; Dicarbethoxydihydrocollidine; Drug-Related Side Effects and Adverse Reactions; Environmental Exposure; Enzyme Activation; Estrogens; Ethanol; Griseofulvin; Heme; Humans; Hydrocarbons, Chlorinated; Iron; Liver; Porphyrias; Porphyrinogens

In liver cells photodamage following externally added protoporphyrin affects predominantly membrane associated components, whereas photodamage by uroporphyrin also affects water-soluble components. Following excess endogenous production of porphyrins, protoporphyrin concentrates in the mitochondria and exerts its photodamaging effect primarily on the mitochondrial system, whereas uroporphyrin concentrates in lysosomes with release and inactivation of lysosomal enzymes when irradiated. The results may be of importance to explain the different skin lesions in porphyria cutanea tarda and erythropoietic protoporphyria.

Topics: Animals; Female; Griseofulvin; Hexachlorobenzene; Humans; Liver; Lysosomes; Male; Middle Aged; Mitochondria, Liver; Photosensitivity Disorders; Porphyrias; Porphyrins; Rats; Rats, Inbred Strains; Skin Diseases

Topics: Animals; Erythropoiesis; Female; Griseofulvin; Liver; Male; Mice; Mice, Inbred Strains; Porphyrias; Protoporphyrins

Treatment of mice with griseofulvin for 8 months induced hepatocellular nodules in the liver which persist after discontinuation of griseofulvin feeding. We investigated the porphyrogenic effect of griseofulvin on these nodules and surrounding nonneoplastic liver after renewed short-term exposure of tumor-bearing mice to this agent. Griseofulvin treatment for 4 days led to marked elevation of the activity of 5-aminolevulinate synthase in peritumoral (3.8-fold) and control (6-fold) liver. The increase in enzyme activity was much less pronounced in the nodules (1.5-fold). Ferrochelatase activity was markedly decreased under the same experimental conditions in both peritumoral and control livers (to 18 and 13.5%, respectively, of the pretreatment values), but the effect was considerably smaller in nodules (to 40% of the pretreatment value). These results may explain the lack of porphyrin accumulation in tumor tissue.

Topics: 5-Aminolevulinate Synthetase; Animals; Diet; Ferrochelatase; Griseofulvin; Heme; Hemin; Liver; Liver Neoplasms; Lyases; Male; Mice; Neoplasms, Experimental; Porphyrias; Protoporphyrins

Topics: Acetamides; Aminolevulinic Acid; Animals; Barbiturates; Cats; Dicarbethoxydihydrocollidine; Dogs; Griseofulvin; Heme; Humans; Hydrocarbons, Halogenated; Hypnotics and Sedatives; Iron; Liver; Liver Diseases; Porphyrias

It has been shown that light may stimulate hepatic porphyria in the rat. This is evidently due to a neuro-endocrine pathway involving retina, nerve pathways in the brain and including the sympathetic chain, the pineal gland and the gonads. This light effect in porphyria appears to be via a circadian rhythm in the liver.

Topics: 5-Aminolevulinate Synthetase; Animals; Circadian Rhythm; Dicarbethoxydihydrocollidine; Female; Griseofulvin; Light; Liver; Male; Mice; Neural Pathways; Ovary; Pineal Gland; Porphyrias; Porphyrins; Rats; Retina; Sex Factors

Topics: 5-Aminolevulinate Synthetase; Animals; Carcinoma, Hepatocellular; Ferrochelatase; Griseofulvin; Liver Neoplasms; Mice; Neoplasms, Experimental; Porphyrias; Protoporphyrins

Miscroscopic changes in the liver tissue of mice became detectable 42 hours after the administration of gricine through the appearance of porphyrins in the plasma of hepatocytes marked by the enlargement of their volume, nuclei, and nucleoli. 72 hours after gricine, porphyrins were also found in the lumina of capilary bile ducts and hepatic ducts. This was accompanied by dispersion extinction of hepatocytes and pigment accumulation in the plasma of Kupffer's cells. There was histochemically proved increased activity of alkaline and acidic phosphatase, G6PDH, NADH and NADPH tetrazolium reductase. Under electron microscopy, the porphyrins showed crystalline structure, rotated the plane of polarized light, and were marked by red fluorescence.

Topics: Animals; Griseofulvin; Liver; Mice; Porphyrias

The changes of delta-aminolaevulinic acid dehydratase--the second enzyme of porphyrin synthesis--were studied and compared in the liver of mice and rats treated with griseofulvin. The results showed that griseofulvin increased the activity of delta-aminolaevulinic acid dehydratase in the liver of mice and rats treated by griseofulvin. No differences were found between mice and rats as to the effect of griseofulvin on the activity of delta-aminolaevulinic acid dehydratase. The influence of the administration of actinomycin D on the activity of delta-aminolaevulinic acid synthetase and dehydratase in the liver of mice and rats was studied at an early period of experimental porphyria induced by griseofulvin. It was found that the administration of actinomycin D blocked the observed effect of griseofulvin on the activity of both enzymes in the liver of mice and rats.

Topics: 5-Aminolevulinate Synthetase; Animals; Dactinomycin; Female; Griseofulvin; Hydro-Lyases; Liver; Mice; Porphobilinogen Synthase; Porphyrias; Rats

Topics: Animals; Chick Embryo; Crystallography; Culture Techniques; Cytoplasmic Granules; Disease Models, Animal; Glucose-6-Phosphatase; Griseofulvin; Liver; Mice; Porphyrias; Protoporphyrins

Topics: Animals; Endothelium; Griseofulvin; Light; Mice; Photosensitivity Disorders; Porphyrias; Porphyrins; Skin

Concentrations of hemopexin, a porphyrin-binding serum protein synthesized exclusively in the liver, increased significantly and concomitantly with levels of erythrocyte and liver protoporphyrin and coproporphyrin in mice made porphyric with 1% griseofulvin in the feed. Liver weights of porphyric mice increased remarkably. In comparison with controls, the ratio of the weight of normal to porphyric livers was at 10 days 1:2.1, at 21 days 1:2.8, and at 46 days 1:3.8. This increase in liver size was accompanied by increased cell division. The hepatic hyperplastic tissue fragments survived in vitro for several weeks and could be subcultured. The cultured cells, like those of the original liver, showed intense protoporphyrin fluorescence in the cytoplasm.

Topics: Animals; Coproporphyrins; Culture Techniques; Erythrocytes; Griseofulvin; Hemopexin; Hyperplasia; Liver; Mice; Organ Size; Porphyrias; Protoporphyrins

Topics: Animals; Cytochrome P-450 Enzyme System; Cytochromes; Griseofulvin; Heme; Male; Mice; Microsomes, Liver; Porphyrias; Regression Analysis; Time Factors

The effect of ethanol, phenobarbitone, griseofulvin or chloroquine on 3,4-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced porphyria in rats has been studied in experiments lasting up to 40 days. Ethanol, phenobarbitone or griseofulvin given later, in addition to DDC, resulted in a clearly greater porphyrin excretion and liver porphyrin concentration than with DDC alone. Chloroquine at first increased, then decreased porphyrin excretion and liver porphyrin was lowered. No drug without DDC was porphyrogenic.

Topics: Animals; Chloroquine; Dicarbethoxydihydrocollidine; Ethanol; Griseofulvin; Liver; Phenobarbital; Porphyrias; Porphyrins; Rats; Time Factors

Excess erythrocyte protoporphyrins of human congenital erythropoietic protoporphyria and of griseofulvin-induced murine hepatic protoporphyria were found to be associated with hemoglobin and stroma fractions in similar relationships. More than 99.5% of total erythrocyte protoporphyrin was bound to hemoglobin in each case. However, profound differences were found when protoporphyrin concentration was measured in erythrocytes that had been segregated into populations of progressive age on discontinuous density gradients. In erythropoietic protoporphyria, porphyrin content diminished rapidly with age; in murine protoporphyria, the aging erythrocyte populations became progressively more porphyrin rich. In vitro diffusion of protoporphyrin from plasma across the intact erythrocyte membrane was demonstrated. The equimolar binding affinity of protoporphyrin to hemoglobin was shown to be 40 times that of protoporphyrin to serum albumin. This strong affinity provides the driving force for the observed transmembrane diffusion, and explains the high erythrocyte/plasma porphyrin ratio in murine hepatic protoporphyria. The opposite rapid efflux of intra-erythrocytic protoporphyrin into plasma previously shown in uncomplicated erythropoietic protoporphyria occurs despite this strong hemoglobin affinity, implying continuous efficient clearance of protoporphyrin from plasma by the liver. Furthermore, these and other data suggest that a hepatic synthetic source for any significant fraction of the blood protoporphyrin in erythropoietic protoporphyria is highly improbable.

Topics: Animals; Binding Sites; Biological Transport; Erythrocytes; Erythropoiesis; Female; Griseofulvin; Hemoglobins; Humans; Lead Poisoning; Mice; Models, Biological; Porphyrias; Porphyrins; Protein Binding; Protoporphyrins; Spectrometry, Fluorescence

Topics: Animals; Erythrocytes; Griseofulvin; Mice; Porphyrias; Porphyrins; Protoporphyrins; Pyridines; Rats

Griseofulvin (GF) feeding of mice resulted in protoporphyria, liver cell damage, bile duct alterations, and finally hepatoma formation. In addition, hepatocellular hyalin developed, resembling in its morphology classic Mallory bodies (MB) as seen in alcoholic and nonalcoholic liver disorders in man. Liver cells containing MB often displayed features of severe cell damage and MB were finally released into the sinusoids and degraded by macrophages. The rapid disappearance of MB following GF discontinuation and the reappearance after resumption of GF feeding suggest an intimate relationship between metabolic alterations in the hepatocytes exerted by the drug and MB formation. This assumption is further supported by the fact that MB change their tinctoreal properties in chromotrope aniline blue-stained sections after GF discontinuation, possibly relfecting degeneration. Long term GF treatment apparently primed the liver for MB formation since the cells were able to respond almost instantly with MB to a GF challenge after a 1-month GF-free period.

Topics: Animals; Bile Ducts; Carcinoma, Hepatocellular; Endoplasmic Reticulum; Griseofulvin; Hyalin; Liver; Liver Neoplasms; Mice; Porphyrias

Albino mice were made protoporphyric with griseofulvin according to an established procedure. Photosensitivity flares were elicited once a week throughout a 10-month period, using black light as a source for 410 nm radiation and the flares were monitored by the intravenous injection of vascular tracers and by light and electron microscopy. Each irradiation led to a selective destruction of the endothelial cells of superficial capillaries which was followed by massive vascular leakage. The basal lamina remained largely intact, providing the scaffold for regenerating endothelial cells which deposited new basal lamina material at their periphery. Subsequent exposures to 410 nm radiation reproduced the endothelial damage and subsequent basal lamina formation; multiple irradiations thus resulted in excessive, concentric, tubelike basal lamina deposits around dermal vessels which light microscopically appeared as PAS-positive hyaline material and clinically gave the skin a thickened, waxy appearance. This model thus reproduced the skin of erythropoietic protoporphyria clinically, microscopically, and at the ultrastructural level.

Topics: Animals; Capillaries; Disease Models, Animal; Erythropoiesis; Female; Griseofulvin; Male; Mice; Photosensitivity Disorders; Porphyrias; Skin; Ultraviolet Rays

Experimental studies on the significance and origin of hepatocellular "alcoholic" hyalin (Mallory bodies) are hampered by the lack of a suitable animal model. In the present paper, the experimental production of hepatocellular hyalin identical with human alcoholic hyalin both light and electron microscopically in long term griseofulvin-treated mice is described. Moreover, the results conclusively disprove the specificity of Mallory alcoholic hyalin for alcohol-induced liver cell damage.

Topics: Alcoholism; Animals; Basement Membrane; Disease Models, Animal; Griseofulvin; Humans; Hyalin; Liver; Liver Cirrhosis, Experimental; Mice; Microscopy, Electron; Porphyrias; Time Factors

Outbred albino mice were rendered protoporphyric by a diet containing 2.5% (weight) of griseofulvin. There was a 5-fold increase in liver weight, hepatocellular degeneration and necrosis, cholestasis, ductular proliferation and cirrhosis. Liver protoporphyrin values were elevated and brown pigment granules were present in hepatocytes, Kupffer cells, and bile ducts. The granules showed red fluorescence, birefringence, and, at the ultrastructural level, consisted of aggregates of needle-like crystals. Crystals isolated from such livers showed solubility and absorption characteristics of protoporphyrin; in vitro recrystallization of protoporphyrin, extracted from protoporphyric mouse livers, yielded crystals identical with those observed in vivo, and commercial protoporphyrin exhibited similar morphologic features. The liver pathology and protoporphyrin crystals observed in these animals are identical to the liver pathology and crystals observed in the human disease, erythropoietic protoporphyria. In this mouse model, protoporphyrin crystals are intimately associated with hepatocellular injury and it appears that their accumulation within hepatocytes leads to hepatocellular destruction. A similar pathogenesis is postulated for the hepatic damage that occurs in some cases of erythropoietic protoporphyria.

Topics: Animals; Bile Ducts; Crystallization; Disease Models, Animal; Erythrocytes; Female; Griseofulvin; Humans; Kupffer Cells; Liver; Male; Mice; Microscopy, Electron; Organ Size; Porphyrias; Porphyrins; Protoporphyrins

The light- and electron-microscopic appearances of a liver biopsy from a case of erythrohepatic protoporphyria are compared with the appearances of the liver in griseofulvin-induced porphyria in mice. Crystals are present in hepatocytes and in the bile secretory pathways in each case. The nature and significance of these is discussed.

Topics: Adult; Animals; Biopsy; Cytoplasm; Endoplasmic Reticulum; Erythrocytes; Feces; Female; Griseofulvin; Humans; Inclusion Bodies; Kupffer Cells; Liver; Liver Function Tests; Male; Mice; Microscopy, Electron; Microscopy, Ultraviolet; Mitochondria, Liver; Phagocytes; Porphyrias; Porphyrins; Skin Tests

Topics: Animals; Barbiturates; Disease Models, Animal; Griseofulvin; Mice; Porphyrias; Porphyrins

1. Drugs such as phenobarbitone and phenylbutazone, which increase the concentration of microsomal haem and cytochrome P-450, also increase the saturation of rat liver apo-(tryptophan pyrrolase) with its haem activator, as does the haem precursor 5-aminolaevulinate. 2. At 4h after the administration of the porphyrogens 2-allyl-2-isopropylacetamide, 3,5-diethoxycarbonyl-1,4-dihydrocollidine and griseofulvin, the total pyrrolase activity is increased whereas the haem saturation of the apoenzyme is decreased. This decreased saturation is prevented by pretreatment of the animals with the inhibitor of drug-metabolizing enzymes, SKF 525-A. 3. Pretreatment of rats with the above porphyrogens inhibits the rise in holo-(tryptophan pyrrolase) activity produced by subsequent administration of cortisol, tryptophan and 5-aminolaevulinate with two single exceptions, the possible reasons for which are discussed. 4. At 24h after the administration, in starved rats, of a single daily injection of the above porphyrogens for 1 or 2 days, the holoenzyme activity is significantly increased. 5. It is suggested that the saturation of rat liver apo-(tryptophan pyrrolase) with its haem activator can be modified by treatment known to cause destruction, inhibition of synthesis, increased utilization and enhanced synthesis of liver haem. The possible involvement of the latter phenomenon in the aetiology of mental disorders in some patients with porphyria is discussed.

Topics: Acetamides; Allylisopropylacetamide; Animals; Apoproteins; Cytochrome P-450 Enzyme System; Dicarboxylic Acids; Griseofulvin; Heme; Humans; Hydrocortisone; Levulinic Acids; Liver; Male; Mental Disorders; Microsomes; Phenobarbital; Phenylbutazone; Porphyrias; Proadifen; Protein Precursors; Pyridines; Rats; Starvation; Time Factors; Tryptophan; Tryptophan Oxygenase

Topics: 5-Aminolevulinate Synthetase; Allylisopropylacetamide; Animals; Dicarboxylic Acids; Esters; Griseofulvin; Heme; Liver; Mice; Phenobarbital; Phenylbutazone; Porphyrias; Pyridines; Rats

Topics: Aspartate Aminotransferases; Erythrocytes; Griseofulvin; Humans; Iron; Liver; Liver Function Tests; Long-Term Care; Onychomycosis; Photosensitivity Disorders; Porphyrias; Porphyrins; Time Factors

Topics: Acetamides; Allyl Compounds; Animals; Cells, Cultured; Chick Embryo; Cycloheximide; Dactinomycin; Depression, Chemical; Glutarates; Glutethimide; Griseofulvin; Heme; Liver; Phthalic Acids; Porphyrias; Porphyrins; Pyridines

Topics: 5-Aminolevulinate Synthetase; Acetamides; Animals; Barbiturates; Chick Embryo; Cytochromes; Griseofulvin; Heme; Liver; Male; Mice; Microsomes, Liver; Mitochondria, Liver; Phenylbutazone; Porphyrias; Porphyrins; Pyridines; Rats

Topics: Antimalarials; Chlordiazepoxide; Contraceptives, Oral; Griseofulvin; Humans; Hypoglycemic Agents; Iatrogenic Disease; Metals; Porphyrias; Urea

Topics: Animals; Enzyme Induction; Erythrocytes; Feces; Griseofulvin; Humans; Hydro-Lyases; Mice; Porphyrias; Porphyrins; Rats; Tinea

Topics: Adolescent; Adult; Aged; Dermatomycoses; Feces; Female; Griseofulvin; Humans; Male; Middle Aged; Porphyrias; Porphyrins

Topics: Australia; Barbiturates; Chloroquine; Cholestyramine Resin; Diet Therapy; Edetic Acid; Estrogens; Griseofulvin; Humans; Porphyrias; Sulfonamides; Sunburn

Topics: Acyltransferases; Animals; Cricetinae; Griseofulvin; Guinea Pigs; Humans; Levulinic Acids; Liver; Liver Cirrhosis; Methods; Mice; Neoplasm Metastasis; Porphyrias; Rats; Spectrophotometry; Succinates

Topics: Alanine Transaminase; Animals; Female; Griseofulvin; Liver; Mice; Porphyrias; Porphyrins

Topics: Acetates; Animals; Carbon Isotopes; Cholesterol; Griseofulvin; Hexachlorocyclohexane; Levulinic Acids; Liver; Male; Mice; Organ Size; Phenobarbital; Porphyrias; Pyridines

Topics: Animals; Anticonvulsants; Barbiturates; Benzene Derivatives; Chick Embryo; Culture Techniques; Dimethyl Sulfoxide; Female; Glutethimide; Griseofulvin; Hexachlorocyclohexane; Liver; Meprobamate; Methods; Mice; Porphyrias; Porphyrins; Pyridines; Time Factors

Topics: Amino Acids; Animals; Barbiturates; Chemical and Drug Induced Liver Injury; Cytochromes; Depression, Chemical; Enzyme Induction; Feedback; Gonadal Steroid Hormones; Griseofulvin; Hexachlorocyclohexane; Levulinic Acids; Ligases; Liver; Male; Mice; Microsomes; Pigments, Biological; Porphyrias; Pyridines; Stimulation, Chemical; Tolbutamide

Topics: Animals; Biotransformation; Cytochromes; Dicumarol; Griseofulvin; Heme; Humans; Liver; Microsomes; Pharmaceutical Preparations; Phenytoin; Porphyrias; Rats

Topics: Aged; Blood Cell Count; Cryoglobulins; Female; Glucose Tolerance Test; Griseofulvin; Humans; Liver; Liver Function Tests; Male; Middle Aged; Porphyrias; Porphyrins; Skin; Skin Manifestations

Topics: Amides; Animals; Chemical Phenomena; Chemistry; Chick Embryo; Culture Techniques; Fluorometry; Glutarates; Glutethimide; Griseofulvin; Liver; Porphyrias; Pyridines; Spectrophotometry; Stereoisomerism

Topics: Animals; Diet; Erythrocytes; Feces; Female; Fertilization; Griseofulvin; Humans; Hydro-Lyases; Iron; Kidney; Ligases; Liver; Male; Mice; Organ Size; Porphyrias; Porphyrins; Pregnancy; Pregnancy, Animal

Topics: Adult; Diet Therapy; Female; Griseofulvin; Humans; Male; Middle Aged; Porphyrias

Topics: Animals; Erythrocytes; Griseofulvin; In Vitro Techniques; Injections, Intraperitoneal; Ligases; Liver; Mice; Porphyrias; Porphyrins; Pyridines; Spleen

Topics: Animals; Cerebral Cortex; Griseofulvin; Hypnotics and Sedatives; Neurons; Porphyrias; Rats; Spinal Cord

Topics: Animals; Antipyrine; Barbiturates; Carbamates; Cattle; Chlordiazepoxide; Chlorobutanol; Culture Techniques; Electron Transport; Glycolysis; Griseofulvin; Hexachlorocyclohexane; Lactates; Mice; Mitochondria; Oxidoreductases; Pharmacology; Porphyrias; Porphyrins; Pyridines; Steroids

Topics: Animals; Griseofulvin; Humans; Liver Diseases; Mice; Onychomycosis; Porphyrias; Porphyrins

Topics: Aged; Griseofulvin; Humans; Lipids; Male; Porphyrias; Porphyrins

Topics: Alcohol Oxidoreductases; Animals; Chlorobutanol; Cholesterol; Glucosephosphate Dehydrogenase; Griseofulvin; Hepatomegaly; Hexobarbital; Hypercholesterolemia; Hypnotics and Sedatives; Lipids; Mice; Porphyrias; Porphyrins

Topics: Drug Therapy; Griseofulvin; Porphyria, Acute Intermittent; Porphyrias; Tinea; Toxicology

Topics: Adenine Nucleotides; Animals; Griseofulvin; Hypoxanthines; Nucleosides; Porphyrias; Rats

Topics: Adult; Contraceptives, Oral; Female; Griseofulvin; Humans; Menstruation Disturbances; Norethandrolone; Porphyrias

Topics: Animals; Glutathione; Griseofulvin; Mice; Porphyrias; Research; Toxicology

Topics: Alanine Transaminase; Clinical Enzyme Tests; Griseofulvin; Liver Function Tests; Porphyria, Acute Intermittent; Porphyrias; Porphyrins; Pyrroles; Toxicology; Urine

Topics: Amino Acids; Catalase; Enzyme Inhibitors; Feces; Griseofulvin; Guinea Pigs; Hexachlorocyclohexane; Lead Poisoning; Levulinic Acids; Liver; Porphyrias; Porphyrins; Pyrroles; Rabbits; Research; Toxicology; Triazoles; Urine

Topics: Adenine Nucleotides; Adenosine; Griseofulvin; Pharmacology; Porphyrias; Rats; Research; Toxicology

Topics: Animals; Griseofulvin; Mice; Porphyrias; Porphyrins

Topics: Animals; Barbiturates; Chemical and Drug Induced Liver Injury; Chick Embryo; Epidemiology; Griseofulvin; Heme; Hepatitis; Hypnotics and Sedatives; Metabolism; Mice; Porphyrias; Porphyrins; Poultry; Pyridines; Rabbits; Rats; Research; Seasons; Toxicology; Turkey; Turkeys