Decrease in 4-Aminobiphenyl-Induced Methemoglobinemia in Cyp1a2(-/-) Knockout Mice

Details

• Personal Author:
  Dalton TP ; Nebert DW ; Shertzer HG ; Talaska G
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Animals Energy Metabolism Hydrocarbons Laboratories Liver Neoplasms Occupational Health Petroleum Polycyclic Aromatic Hydrocarbons Safety Skin

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• Keywords:
  Animal-studies Cancer Hepatotoxicity Laboratory-animals Liver-disorders Metabolic-study Petroleum-products Polycyclic-aromatic-hydrocarbons Polycyclic-hydrocarbons Skin-exposure
• ISSN:
  0041-008X
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Ohio ; OSHA Region 5
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  32-37
• Volume:
  181
• Issue:
  1
• NIOSHTIC Number:
  nn:20029587
• Citation:
  Toxicol Appl Pharmacol 2002 May; 181(1):32-37
• Contact Point Address:
  Department of Environmental Health, Center for Environment Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056
• Email:
  shertzhg@ucmail.uc.edu
• Federal Fiscal Year:
  2002
• NORA Priority Area:
  Research Tools and Approaches: Risk Assessment Methods
• Performing Organization:
  University of Cincinnati, Cincinnati, Ohio
• Peer Reviewed:
  True
• Start Date:
  19990930
• Source Full Name:
  Toxicology and Applied Pharmacology
• End Date:
  20030929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:02430c2433af1225920e72e90de4e6f248ce555a1cfbeba6af2dfc022d7183d712bad39873564353f70106de15c776cdf9d54dcf2671308c4ab32679443cebf5
• Download URL:
  https://stacks.cdc.gov/view/cdc/190536/cdc_190536_DS1.pdf
• File Type:
  [PDF - 111.38 KB ]