Induction of cytochrome P-450-dependent monooxygenases by isoniazid in hamster liver, kidney and lung.
The effects of isoniazid on liver, kidney, and lung monooxygenases were determined using hamsters administered 0.8% of the antituberculosis drug in drinking water. Binding of isoniazid to liver microsomal cytochrome P-450 induced a Type II difference spectrum and the spectral binding was enhanced in hamsters treated with isoniazid. The levels of cytochrome P-450, NADPH-cytochrome c reductase, and cytochrome b5 in the tissues microsomes from isoniazid-treated hamsters were similar to the respective levels in control animals. In the liver, treatment with isoniazid caused 5- and 3-fold induction of aniline hydroxylase and N-nitrosodimethylamine demethylase activities, respectively. The treatment was without effect on hepatic benzo(a)pyrene hydroxylase or 7-ethoxycoumarin O-deethylase activities. In the kidneys, isoniazid treatment caused 6-, 2-fold, and 42% increases in monooxygenase activities toward aniline, N-nitrosodimethylamine, and 7-ethoxycoumarin, respectively. However, the treatment caused a 15% decrease in renal benzo(a)pyrene hydroxylase activity. In the lungs, isoniazid caused a 69% increase in aniline hydroxylase and, in contrast, a 30% decrease in 7-ethoxycoumarin O-deethylase activities. The treatment had no significant effects on pulmonary catalytic activities toward N-nitrosodimethylamine and benzo(a)pyrene. Gel electrophoresis of liver and kidney microsomes from control and isoniazid-treated hamsters revealed that the treatment increased the intensity of a protein band in the P-450 molecular weight region. Immunoblotting of microsomal proteins showed that the protein band induced by isoniazid in the liver, kidney and lung was cross-reactive with antibody raised against ethanol-inducible human liver P-450.(ABSTRACT TRUNCATED AT 250 WORDS)
Institutes of Toxicology and Biochemistry, College of Medicine, National Taiwan University, Taipei, R.O.C.
T H
TH
Ueng
Y F
YF
Ueng
D000818:Animals; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D007538:Isoniazid / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology*; D008168:Lung / Q000201:enzymology*; D008297:Male; D008647:Mesocricetus; D010105:Oxygenases / Q000096:biosynthesis*
D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D007538:Isoniazid