Decrease in 4-aminobiphenyl-induced methemoglobinemia in Cyp1a2(-/-) knockout mice.
Methemoglobin formation, as well as hemoglobin or DNA adducts, are useful biomarkers of occupational exposure to certain arylamines. It has been suggested that, in liver from animals not treated with a cytochrome P450 (CYP) inducer, hepatic CYP1A2 is the major P450 involved in N-hydroxylation. This is the first step in the metabolic activation of many arylamines, such as the human urinary bladder carcinogen 4-aminobiphenyl (ABP). The product of this catalytic step, N-hydroxy-4-ABP, reacts in the blood with oxyhemoglobin to form methemoglobin and nitrosobiphenyl. We therefore examined the role of CYP1A2 in causing methemoglobinemia in ABP-treated Cyp1a2(-/-) knockout mice. Application of ABP (100 micromol/kg body wt) to the skin resulted in a marked depletion in the levels of the hepatic thiols (reduced glutathione and cysteine) after 2 h, which rebounded to basal levels 24 h later, and we found no differences between the Cyp1a2(-/-) and wild-type Cyp1a2(+/+) animals. Unexpectedly, the methemoglobin levels were significantly (p < 0.05) higher in Cyp1a2(-/-) than Cyp1a2(+/+) mice at 2, 7, and 24 h following topical ABP. Treatment with dioxin, 24 h prior to ABP, decreased methemoglobin levels by about half at each of the time points in both the Cyp1a2(-/-) and Cyp1a2(+/+) mice. These data suggest that CYP1A2 does not play a positive role in methemoglobin formation via the activation of ABP; rather, the absence of CYP1A2 enhances ABP-induced methemoglobinemia. Because liver CYP1A2 levels are known to vary more than 60-fold between humans, our findings may be relevant to patients who are exposed to arylamines in the workplace.
Shertzer
Howard G
HG
Department of Environmental Health, Center for Environment Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, USA. shertzhg@ucmail.uc.edu
Dalton
Timothy P
TP
Talaska
Glenn
G
Nebert
Daniel W
DW
D000287:Administration, Topical; D000611:Aminobiphenyl Compounds / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D015415:Biomarkers; D001711:Biotransformation; D002273:Carcinogens / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D003545:Cysteine / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008708:Methemoglobinemia / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016273:Occupational Exposure; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism / Q000633:toxicity
D000611:Aminobiphenyl Compounds; D015415:Biomarkers; D002273:Carcinogens; D000072317:Polychlorinated Dibenzodioxins; C006757:4-biphenylamine; D019388:Cytochrome P-450 CYP1A2; D005978:Glutathione; D003545:Cysteine