Mutat Res. 1992 Dec 16;284(2):233-41.  

Rat pulmonary microsomal cytochrome P-450 enzymes involved in the activation of
procarcinogens.

Shimada T, Yamazaki H, Mimura M, Guengerich FP.

Osaka Prefectural Institute of Public Health, Japan.

Rat lung microsomal cytochrome P-450 (P-450) enzymes have been characterized
with regard to their catalytic specificities towards activation of several
procarcinogens to genotoxic metabolites in Salmonella typhimurium
TA1535/pSK1002. We first examined the roles of rat liver microsomal P-450
enzymes in the activation of benzo[a]pyrene and its 7,8-diol enantiomers to
genotoxic products, and found that P-450 1A1 is a major catalyst for the
activation of these potential procarcinogens in rat livers. Using lung
microsomes isolated from rats treated with various P-450 inducers we obtained
evidence that at least three P-450 enzymes are involved in the activation of
several procarcinogens. Immunoinhibition studies support the view that
benzo[a]pyrene and its 7,8-diol derivatives, other dihydrodiol derivatives of
polycyclic aromatic hydrocarbons, and 3-amino-1-methyl-5H-pyrido[4,3-b]indole
are activated to genotoxins mainly by rat P-450 1A1, which is inducible in rat
lungs by 5,6-benzoflavone and the polychlorinated biphenyl mixture Aroclor 1254.
Activation of 2-amino-3,5-dimethylimidazo[4,5-f]quinoline and
2-amino-3-methylimidazo[4,5-f]quinoline may be catalyzed by another P-450 enzyme
because the activities were not induced by treatment with 5,6-benzoflavone or
Aroclor 1254. The observation that both activities were inhibited by antibodies
raised against P-450 1A2 and by 7,8-benzoflavone suggests a role for an enzyme
of P-450 1A family, probably P-450 1A2, in rat lung microsomes. The activation
of aflatoxin B1 and sterigmatocystin appears to be catalyzed by other P-450
enzyme(s) rather than the P-450 1A family as judged by the different responses
of activities to the P-450 inducers and the specific antibodies in rat lung
microsomes. Interestingly, lung microsomal activation of several procarcinogens
was found to be suppressed in rats treated with isosafrole and pregnenolone 16
alpha-carbonitrile. Thus, the results support the roles of different P-450
enzymes in the activation of procarcinogens in rat lung microsomes.

PMID: 1281274 [PubMed - indexed for MEDLINE]