Pyridine induction of cytochrome P-450 in the rat: role of P-450j (alcohol-inducible form) in pyridine N-oxidation.
Previous research has shown that pyridine (PY) pretreatment of rabbits elevates total hepatic microsomal cytochrome P-450 content in association with the appearance of intense bands in the region of P-450LM4 and LM3 in the electrophoretic pattern of the microsomes and increased rates of PY N-oxide production and N-nitrosodimethylamine, alcohol and aniline metabolism. In the present study, PY administration (100 mg/kg i.p., 4 days) to rats was found to elevate hepatic microsomal cytochrome P-450 content approximately 2.5-fold as compared to controls. Sodium dodecylsulfate-polyacrylamide gel electrophoresis revealed a protein band of enhanced intensity migrating in the region of P-450j, the major ethanol-inducible form of rat liver cytochrome P-450. Immunochemical analysis confirmed that the level of immunoreactive P-450j protein was increased in PY-induced microsomes as compared to preparations from control, phenobarbital- or beta-naphthoflavone-induced animals. The rate of PY N-oxide production was enhanced 4-fold in PY-induced microsomes relative to untreated controls and was approximately 1.5- to 2-fold greater than that monitored for either phenobarbital- or beta-naphthoflavone-induced microsomes. When data were normalized for increased P-450 content, an altered substrate specificity was suggested for the PY-induced microsomes. para-Nitrophenol hydroxylase activity, which is exhibited primarily by the ethanol-inducible form of P-450, was elevated approximately 4-fold in PY-induced microsomes relative to uninduced microsomes and, when expressed per nanomol of P-450, was approximately 2- to 3-fold greater in PY-induced preparations as compared to phenobarbital-, beta-naphthoflavone-induced, or uninduced microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois.
S G
SG
Kim
D E
DE
Williams
E G
EG
Schuetz
P S
PS
Guzelian
R F
RF
Novak
D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D007527:Isoenzymes / Q000096:biosynthesis*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D007527:Isoenzymes; D011725:Pyridines; D003577:Cytochrome P-450 Enzyme System; C013229:pyridine N-oxide; D019392:Cytochrome P-450 CYP2E1; D000815:Aniline Hydroxylase; D010089:Oxidoreductases, N-Demethylating; C023666:pyridine