CYP1A2 is not the primary enzyme responsible for 4-aminobiphenyl-induced hepatocarcinogenesis in mice.
4-Aminobiphenyl (4-ABP), a potent carcinogen in rodents (liver cancer) and human (bladder cancer), is found as an environmental contaminant and in tobacco smoke. Hemoglobin adducts and lung DNA adducts of 4-ABP are found in tobacco smokers. In vitro metabolism studies with human and rat liver microsomes have shown that CYP1A2 is primarily responsible for catalyzing N-hydroxylation, the initial step in the metabolic activation of 4-ABP. To determine whether this P450 is a rate limiting pathway for hepatocarcinogenesis, CYP1A2-null mice were analyzed at 16 months of age and were compared with wild-type mice in their response to 4-ABP using the neonatal mouse bioassay and two different doses of the carcinogen. Overall differences in incidences of hepatocellular adenoma, carcinoma and preneoplastic foci were not significant between either genotypes or 4-ABP doses used, whereas small, but significant, differences were found for specific types of foci. These results suggest that while CYP1A2 levels may not be rate limiting for 4-ABP metabolism to produce tumors and foci, it may modulate the induction process of some types of liver foci in either a positive or negative manner. In vitro studies using CYP1A2-null and wild-type mouse liver microsomes revealed that CYP1A2 is not the sole P450 required for 4-ABP N-hydroxylation and that another, yet to be identified, P450 is likely to be involved.
Kimura
S
S
Laboratory of Metabolism, National Cancer Institute, Bethesda, MD 20892, USA. shioko@helix.nih.gov
Kawabe
M
M
Ward
J M
JM
Morishima
H
H
Kadlubar
F F
FF
Hammons
G J
GJ
Fernandez-Salguero
P
P
Gonzalez
F J
FJ
D000236:Adenoma / Q000139:chemically induced / Q000201:enzymology; D000611:Aminobiphenyl Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D001711:Biotransformation; D002274:Carcinogens, Environmental / Q000493:pharmacokinetics / Q000633:toxicity*; D002277:Carcinoma / Q000139:chemically induced / Q000201:enzymology; D003433:Crosses, Genetic; D019388:Cytochrome P-450 CYP1A2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D006801:Humans; D006900:Hydroxylation; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000201:enzymology*; D009929:Organ Size / Q000187:drug effects; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000235:genetics; D013045:Species Specificity; D013270:Stomach / Q000201:enzymology / Q000473:pathology
D000611:Aminobiphenyl Compounds; D002274:Carcinogens, Environmental; D018336:Receptors, Aryl Hydrocarbon; C014970:2-aminodiphenyl; D019388:Cytochrome P-450 CYP1A2