Selective induction of cytochrome P450 isozymes in rat liver by 4-n-alkyl-methylenedioxybenzenes.
To examine the structural requirements of cytochrome P450 induction by 4-n-alkyl-substituted methylenedioxybenzenes (MDBs), rats were treated in vivo with a series of MDBs that differed in alkyl carbon side-chain length (0, 1, 2, 3, 4, 5, 6, or 8). Expression patterns of specific P450 isozymes were evaluated with Western and Northern blotting, enzymatic assays, and solution hybridization assays. As determined by carbon monoxide difference spectroscopy, maximal hepatic induction of total P450 content occurred when rats were treated with MDB derivatives with alkyl chain lengths of five or six carbons. However, maximum induction of the specific P450s--P450IA1, P450IIB1, and P450IIB2--occurred with n-hexyl-MDB. In contrast to effects observed with phenobarbital, treatment with MDBs resulted in higher levels of P450IIB2 than of P450IIB1 in rat hepatic microsomes. Western blot quantitation of MDB-induced hepatic P450IIB1 and P450IIB2 apoenzymes did not correlate to measured levels of the corresponding P450 mRNAs. In fact, P450IIB1 and P450IIB2 apoenzyme levels were consistently lower than expected based on Northern blot and solution hybridization measures of the respective mRNAs. These data suggest that the n-alkyl-MDBs effect increases in levels of hepatic P450 in a complex manner, producing accumulation of P450 mRNAs concomitant with alterations in processes regulating steady-state levels of P450 apoenzyme.
Marcus
C B
CB
Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
Wilson
N M
NM
Jefcoate
C R
CR
Wilkinson
C F
CF
Omiecinski
C J
CJ
D000478:Alkylation; D000818:Animals; D001051:Apoenzymes / Q000096:biosynthesis / Q000235:genetics; D001483:Base Sequence; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004790:Enzyme Induction; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D010634:Phenobarbital / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D001051:Apoenzymes; D001555:Benzene Derivatives; D007527:Isoenzymes; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital