Carcinogenesis. 1991 Jan;12(1):133-9.  

Roles of different cytochrome P450 enzymes in bioactivation of the potent
hepatocarcinogen 3-methoxy-4-aminoazobenzene by rat and human liver microsomes.

Yamazaki H, Degawa M, Funae Y, Imaoka S, Inui Y, Guengerich FP, Shimada T.

Osaka Prefectural Institute of Public Health, Japan.

The potent hepatocarcinogen 3-methoxy-4-aminoazobenzene (3-MeO-AAB) has been
reported to be bioactivated to mutagenic intermediates by rat liver microsomal
cytochrome P450 (P450) and to be a selective inducer of rat P450IA2. In this
study we have further investigated the roles of individual rat and human P450
enzymes in the bioactivation of this hepatocarcinogen in a Salmonella
typhimurium TA1535/pSK1002 system where umu response is indicative of DNA
damage. 3-MeO-AAB was found to be bioactivated by liver microsomal enzymes from
rats and humans in this assay system. The liver microsomal activities are
increased by pretreatment of rats with various P450 inducers such as
phenobarbital (PB), beta-naphthoflavone (BNF), dexamethasone (DEX), acetone,
ethanol, isoniazid (INH), diphenylhydantoin and valproic acid, and can be
inhibited considerably by SKF-525A and metyrapone. alpha-Naphthoflavone (ANF) is
also an inhibitor for the reaction catalyzed in BNF-treated rats, but stimulated
the microsomal activity in DEX-treated rats. Evidence has also been obtained
that specific antibodies raised against P450IIB1, P450IA1 or IA2, P450IIE1, and
P450IIIA2 inhibited the activation in liver microsomes from rats pretreated with
PB, BNF, INH and DEX respectively, suggesting the possible roles of several P450
enzymes in the bioactivation of 3-MeO-AAB. The results obtained with
reconstituted monooxygenase systems containing various rat P450 enzymes are
highly supportive of this conclusion. Human liver microsomal activation of
3-MeO-AAB was also inhibited to various extents by antibodies raised against
P450IA2, P450MP, P450IIE1 and P450IIIA4. In a reconstituted system containing
purified forms of human P450, P450IA2 was the most active in catalyzing
3-MeO-AAB, followed by P450IIIA4 and P450MP. ANF, a known activator of
P450IIIA-catalyzed reactions, caused an increase in activation of 3-MeO-AAB in
human liver microsomal and P450IIIA4- and P450MP-containing reconstituted
systems. From these results it is concluded that multiple P450 enzymes in rat
and human liver microsomes are involved in the bioactivation of 3-MeO-AAB,
regardless of its selective induction of the rat P450IA2 gene.

PMID: 1988174 [PubMed - indexed for MEDLINE]