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.