griseofulvin and Porphyria--Acute-Intermittent

(1) We evaluated the involvement of brain mitochondrial and microsomal cytochrome P-450 in the metabolization of known porphyrinogenic agents, with the aim of improving the knowledge on the mechanism leading to porphyric neuropathy. We also compared the response in brain, liver and kidney. To this end, we determined mitochondrial and microsomal cytochrome P-450 levels and the activity of NADPH cytochrome P-450 reductase. (2) Animals were treated with known porphyrinogenic drugs such as volatile anaesthetics, allylisopropylacetamide, veronal, griseofulvin and ethanol or were starved during 24 h. Cytochrome P-450 levels and NADPH cytochrome P-450 reductase activity were measured in mitochondrial and microsomal fractions from the different tissues. (3) Some of the porphyrinogenic agents studied altered mitochondrial cytochrome P-450 brain but not microsomal cytochrome P-450. Oral griseofulvin induced an increase in mitochondrial cytochrome P-450 levels, while chronic Isoflurane produced a reduction on its levels, without alterations on microsomal cytochrome P-450. Allylisopropylacetamide diminished both mitochondrial and microsomal cytochrome P-450 brain levels; a similar pattern was detected in liver. Mitochondria cytochrome P-450 liver levels were only diminished after chronic Isoflurane administration. In kidney only mitochondrial cytochrome P-450 levels were modified by veronal; while in microsomes, only acute anaesthesia with Enflurane diminished cytochrome P-450 content. (4) Taking into account that delta-aminolevulinic acid would be responsible for porphyric neuropathy, we investigated the effect of acute and chronic delta-aminolevulinic acid administration. Acute delta-aminolevulinic acid administration reduced brain and liver cytochrome P-450 levels in both fractions; chronic delta-aminolevulinic acid administration diminished only liver mitochondrial cytochrome P-450. (5) Brain NADPH cytochrome P-450 reductase activity in animals receiving allylisopropylacetamide, dietary griseofulvin and delta-aminolevulinic acid showed a similar profile as that for total cytochrome P-450 levels. The same response was observed for the hepatic enzyme. (6) Results here reported revealed differential tissue responses against the xenobiotics assayed and give evidence on the participation of extrahepatic tissues in porphyrinogenic drug metabolization. These studies have demonstrated the presence of the integral Phase I drug metabolizing system in the brain, thus, total

Topics: Allylisopropylacetamide; Aminolevulinic Acid; Animals; Barbital; Brain; Cytochrome P-450 Enzyme System; Ethanol; Griseofulvin; Hypnotics and Sedatives; Kidney; Liver; Male; Metabolic Detoxication, Phase I; Mice; Microsomes; Mitochondria; NADPH-Ferrihemoprotein Reductase; Photosensitizing Agents; Porphyria, Acute Intermittent

Several drugs and stress are involved in the triggering of attacks in acute porphyrias. The central nervous system is extremely sensitive to free radical damage because of a relatively low antioxidant capacity. We have demonstrated that mice brain cholinergic system was altered by the effect of some porphyrinogenic agents. The aim of this work was to investigate how known porphyrinogenic drugs affect delta-Aminolevulinic acid synthetase (ALA-S), which is the response of heme oxygenase (HO) to this challenge and to evaluate if the xenobiotics studied develop stress oxidative in mice brain. HO activity was 50-70% induced after chronic Enflurane and Isoflurane anaesthesia, dietary Griseofulvin and starvation. An increase in mRNA HO expression was caused by chronic anaesthesia and Veronal treatments; instead allylisopropilacetamide (AIA) reduced mRNA expression. ALA-S activity was induced by acute administration of anaesthetics (89%), veronal (240%) and ethanol (80%), while ALA-S mRNA expression augmented by chronic administration of enflurane, AIA and veronal. Stress markers such as superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities and malondialdehyde and reduced glutathione levels showed different responses depending on the xenobiotic assayed. In conclusion, some of the drugs studied produced oxidative stress in brain that was confirmed through HO induction and this could be one of the factors leading to porphyric neuropathy.

Topics: 5-Aminolevulinate Synthetase; Animals; Antioxidants; Barbital; Brain; Enflurane; Ethanol; Gene Expression Regulation, Enzymologic; Griseofulvin; Heme Oxygenase (Decyclizing); Isoflurane; Male; Mice; Mice, Inbred Strains; Oxidative Stress; Porphyria, Acute Intermittent; Porphyrinogens; RNA, Messenger

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

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