Ethanol and isoniazid induce a hepatic microsomal cytochrome P-450-dependent activity with similar properties towards substrate and inhibitors and different properties from those induced by classical inducers.
Male Wistar rats were pretreated with chronic ethanol ingestion (3 weeks), phenobarbital in the drinking water (1 week), beta naphtoflavone or trans-stilbene oxide (one daily i.p. injection for 3 days) or isoniazid (one daily i.p. injection for 7 days). All these treatments increased 4-nitroanisole O-demethylase activity above the control level. Kinetic studies indicated that ethanol and isoniazid induction gave low apparent K0.5 (less than 0.1 mM), trans-stilbene oxide and phenobarbital intermediate (0.1 mM less than K0.5 less than 0.5 mM) and beta naphtoflavone high K0.5 (greater than 0.5 mM) for the induced activities. Inhibition studies with 0.1 mM metyrapone, 0.1 mM imidazole or 5 mM 1,3-dioxolane provided further evidence that the induced activities had different properties. Differences were also observed in the subtypes of spectral type II interaction (IIa and IIb) with 0.1 mM imidazole or 0.1 mM metyrapone in the induced microsomes. The results indicate that demethylation of 4-nitroanisole is an effective reaction for distinguishing between three different types of cytochrome P-450 induction. The clinically important hepatotoxins ethanol and isoniazid appeared to induce the same type of cytochrome P-450 activity, and it is speculated that these toxins may predispose to hepatotoxicity by means of this common property.
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004148:Dioxolanes / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D007538:Isoniazid / Q000494:pharmacology*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology*; D010090:Oxidoreductases, O-Demethylating / Q000032:analysis; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013053:Spectrophotometry
D004148:Dioxolanes; D007093:Imidazoles; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; C026048:4-nitroanisole O-demethylase; D010090:Oxidoreductases, O-Demethylating; D007538:Isoniazid; D010634:Phenobarbital; D008797:Metyrapone