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Decrease in 4-aminobiphenyl-induced methemoglobinemia in Cyp1a2(-/-) knockout mice.

Authors
Shertzer-HG; Dalton-TP; Talaska-G; Nebert-DW
Source
Toxicol Appl Pharmacol 2002 May; 181(1):32-37
NIOSHTIC No.
20029587
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.
Keywords
Polycyclic-aromatic-hydrocarbons; Polycyclic-hydrocarbons; Skin-exposure; Petroleum-products; Animal-studies; Animals; Laboratory-animals; Metabolic-study; Liver-disorders; Cancer; Hepatotoxicity
Contact
Department of Environmental Health, Center for Environment Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056
CODEN
TXAPA9
Publication Date
20020515
Document Type
Journal Article
Email Address
shertzhg@ucmail.uc.edu
Funding Amount
690180
Funding Type
Grant
Fiscal Year
2002
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-004124
Issue of Publication
1
ISSN
0041-008X
Priority Area
Research Tools and Approaches: Risk Assessment Methods
Source Name
Toxicology and Applied Pharmacology
State
OH
Performing Organization
University of Cincinnati, Cincinnati, Ohio
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