Consequences of 3-methylcholanthrene-type induction for the metabolism of 4-aminobiphenyl in isolated rat hepatocytes.
Carcinogenic aromatic amines such as 4-aminobiphenyl (4-ABP) are extensively metabolized by both oxidative and conjugation reactions. Thus the burden of genotoxic metabolites of 4-ABP in a target organ is probably influenced by the balance of N-hydroxylation and alternative metabolic pathways in the hepatocyte. In freshly isolated rat hepatocytes, 4-ABP (at a substrate concentration of 10 microM) was mainly N-acetylated (54% of total metabolites), while 2% N-hydroxy-4-ABP-N-glucuronide and 21% of unconjugated N-hydroxylated metabolites were detectable. Ring-hydroxylated metabolites and the primary N-glucuronide of 4-ABP accounted for 8% and 4%, respectively. Pretreatment of rats with 3-methylcholanthrene (MC), a dioxin-type inducer of CYP1A isozymes and phenol UDP-glucuronosyltransferase (UGT1A1), led to a dramatic decrease of N-acetylated (2% of total metabolites) and an increase of N-hydroxylated (54% as free and glucuronidated compound) and ring-hydroxylated (35%) metabolites. Essentially similar effects were seen at a substrate concentration of 50 microM. Consistently, MC-type induction with beta-naphthoflavone resulted in a significant increase in the formation of DNA adducts of 4-ABP, detected by 32P-postlabeling of hepatocellular DNA. The results suggest that, similar to a previous study with 2-naphthylamine (2-NA), MC treatment leads to a marked shift from conjugation to N-oxidation. However, N-hydroxy-4-ABP (in contrast to N-hydroxy-2-NA) is mostly released from hepatocytes in the unconjugated form.
Orzechowski
A
A
Institute of Toxicology, University of Tübingen, Germany.
Schrenk
D
D
Schut
H A
HA
Bock
K W
KW
D000611:Aminobiphenyl Compounds / Q000378:metabolism*; D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000611:Aminobiphenyl Compounds; D002273:Carcinogens; C006757:4-biphenylamine; D008748:Methylcholanthrene; D004247:DNA