thioacetamide and cobaltous-chloride

The effects of pyrazole, which is known to induce hepatic cytochrome P4502A5 (CYP2A5) through posttranscriptional mechanisms, on the level of CYP2A5 in liver and extrahepatic tissues were examined in this study. Intraperitoneal administration of pyrazole at 200 mg/kg for 3 days induced CYP2A4/5 mRNAs and proteins and microsomal coumarin 7-hydroxylation activity in liver and kidney of C57BL/6 mice. A marginal increase (30%) in CYP2A4/5 mRNAs was also observed in the olfactory mucosa but not in the lung, and no increase in CYP2A4/5 proteins or microsomal coumarin 7-hydroxylation activity was observed in either the olfactory mucosa or lung. CYP2A4/5 proteins were not detected on immunoblots in other tissues examined, including breast, bone marrow, testis, prostate, ovary, and uterus from control or pyrazole-treated mice. On the other hand, pyrazole treatment induced CYP2E1 in the olfactory mucosa as well as in liver and kidney, indicating that the olfactory mucosa was exposed to pyrazole. The lack of CYP2A inducibility in the olfactory mucosa was also observed for several other known inducers of hepatic CYP2A5, including cobaltous chloride, stannous chloride, griseofulvin, thioacetamide, and aminotriazole. These results suggest that the mechanisms involved in the induction of hepatic and renal CYP2A5 by pyrazole and other xenobiotic compounds may be tissue-specific.

Topics: Amitrole; Animals; Aryl Hydrocarbon Hydroxylases; Cobalt; Coumarins; Cytochrome P-450 CYP2A6; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 2; DNA Probes; Enzyme Induction; Griseofulvin; Immunoblotting; Isoenzymes; Kidney; Liver; Lung; Male; Mice; Mice, Inbred C57BL; Mixed Function Oxygenases; Olfactory Mucosa; Pyrazoles; RNA, Messenger; Substrate Specificity; Thioacetamide; Tin Compounds; Xenobiotics

The level of rat hepatic ornithine decarboxylase (ODC) induced by repetitive administration of Co2+ was determined by affinity labeling with [3H]difluoromethylornithine. Such a treatment with Co2+ ion induced ODC level to a 10-fold greater extent than single dose of the metal ion or well-known inducers of the enzyme, such as thioacetamide or carbon tetrachloride. The half life of ODC activity induced by repetitive treatment with Co2+ (95 min) was substantially increased to about 10-fold over the value obtained from the enzyme induced by single treatment with the metal ion (10 min). ODC activity induced by repetitive treatment with Co2+ was separated into two peaks by DEAE-Sepharose column chromatography. The two independently collected fractions of ODC peaks exhibited different affinity for pyridoxal 5'-phosphate in vitro and sensitivity to cycloheximide in vivo.

Topics: Animals; Carbon Tetrachloride; Cobalt; Cycloheximide; Drug Administration Schedule; Drug Synergism; Enzyme Induction; Injections, Subcutaneous; Kinetics; Liver; Male; Ornithine Decarboxylase; Rats; Rats, Inbred Strains; Reference Values; Thioacetamide

Inhibitors of heme biosynthesis such as CoCl2, 3-amino-1,2,4-triazole, and thioacetamide block the 3-methylcholanthrene-mediated induction of cytochrome P-450 (c + d) messenger RNAs and their transcription in rat liver. This effect is specific, since the messenger RNA levels for albumin and glutathione transferase (Ya + Yc) and their transcription are not significantly influenced under conditions of heme depletion. Exogenous administration of heme at very low doses (50 micrograms/100 g body wt) is able to completely counteract the effects of the heme biosynthetic inhibitors on cytochrome P-450 (c + d) messenger RNA levels and their transcription. This constitutes a direct proof for the role of heme as a positive regulator of cytochrome P-450 gene transcription.

Topics: Amitrole; Animals; Base Sequence; Cobalt; Cytochrome P-450 Enzyme System; DNA; DNA, Recombinant; Heme; Male; Methylcholanthrene; Molecular Sequence Data; Nucleic Acid Hybridization; Rats; RNA, Messenger; Thioacetamide; Transcription, Genetic

Aminophenazone, phenazone, propyphenazone, and paracetamol given to female Wistar rats in a dose of 3 mmol/kg decrease the GSH content in the liver by 24, 18, 58, and 24 per cent, respectively. After the repeated administration (5 days) only aminophenazone depletes the hepatic GSH. The pretreatment with phenobarbital or cobaltous chloride has an influence only on the effect of propyphenazone. Hepatotoxins cause more extensive hepatotoxic alterations than the drugs investigated, however, their influence on the hepatic GSH level is negligible. Therefore it can be concluded that a temporary GSH depletion is not always linked with a hepatotoxic effect.

Topics: 1-Propanol; Acetaminophen; Aminopyrine; Animals; Antipyrine; Carbon Tetrachloride; Cobalt; Female; Glutathione; Liver; Phenobarbital; Propanols; Pyrazoles; Rats; Rats, Inbred Strains; Thioacetamide