title: Decrease in 4-aminobiphenyl-induced methemoglobinemia in Cyp1a2(-/-) knockout mice.
abstract: 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.
authors.affiliation: Department of Environmental Health, Center for Environment Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, USA. shertzhg@ucmail.uc.edu
authors.forename: Howard G
authors.initials: HG
authors.lastname: Shertzer
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Dalton
authors.forename: Glenn
authors.initials: G
authors.lastname: Talaska
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
mesh_terms: 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
chemical_list: D000611:Aminobiphenyl Compounds; D015415:Biomarkers; D002273:Carcinogens; D000072317:Polychlorinated Dibenzodioxins; C006757:4-biphenylamine; D019388:Cytochrome P-450 CYP1A2; D005978:Glutathione; D003545:Cysteine