Inhibition and induction of rabbit liver microsomal cytochrome P-450 by pyridine

The effects of acute and chronic administration of pyridine (PY) on rabbit hepatic microsomal cytochrome P-450-catalyzed drug metabolism have been examined. PY inhibited cytochrome P-450-catalyzed drug metabolism in vitro and in vivo. Noncompetitive inhibition of microsomal drug metabolism was observed with inhibitory constant (Ki) values ranging between 2.0 and 6.0 mM. Acute PY administration, 100 mg/kg i.p., prolonged hexobarbital sleep time in rats 2.5-fold. Chronic administration of PY to rabbits resulted in increased hepatic microsomal cytochrome P-450 content, with induction of different form(s) exhibiting elevated catalytic activities toward PY, N-nitrosodimethylamine, alcohols and aniline. PY administration (100 mg/kg i.p. for 5 days) to rabbits increased hepatic microsomal cytochrome P-450 content over 2-fold relative to uninduced animals. Sodium dodecylsulfate-polyacrylamide gel electrophoresis of PY-induced microsomes revealed protein bands of enhanced intensity occurring in the regions of P-450 LM3 and LM4. Both PY- and imidazole-induced microsomes were effective in the production of PY N-oxide, with Vmax values of 1.6 and 1.8 nmol/min/mg of protein, respectively. When rates were normalized for P-450 content, PY- and imidazole-induced microsomes produced 0.9 nmol of PY N-oxide/min/nmol of P-450, comparable to that obtained for PB-induced suspensions. N-nitrosodimethylamine N-demethylase activity was enhanced 2.5- and 6-fold relative to PB- and beta-naphthoflavone-induced microsomes, respectively. A single low KM value of 0.17 mM was obtained for N-nitrosodimethylamine N-demethylase activity in PY-induced microsomes; in contrast PB- and beta-naphthoflavone-induced microsomes yielded biphasic kinetics.(ABSTRACT TRUNCATED AT 250 WORDS)