Interindividual Variance of Cytochrome P450 Forms in Human Hepatic Microsomes: Correlation of Individual Forms with Xenobiotic Metabolism and Implications in Risk Assessment

Details

• Personal Author:
  Lipscomb JC ; Snawder, John E.
• Description:
  Differences in biotransformation activities may alter the bioavailability or efficacy of drugs, provide protection from certain xenobiotic and environmental agents, or increase toxicity of others. Cytochrome P450 (CYP450) enzymes are responsible for the majority of oxidation reactions of drugs and other xenobiotics and differences in their expression may directly produce interindividual differences in susceptibility to compounds whose toxicity is modulated by these enzymes. To rapidly quantify CYP450 forms in human hepatic microsomes, we developed, and applied, an ELISA to 40 samples of microsomes from adult human organ donors. The procedure was reliable and the results were reproducible within normal limits. Protein content for CYP1A, CYP2E1, and CYP3A positively correlated with suitable marker activities. CYP1A, CYP2B, CYP2C6, CYP2C11, CYP2E1, and CYP3A protein content demonstrated 36-, 13-, 11-, 2-, 12-, and 22-fold differences between the highest and lowest samples and the values were normally distributed. Of the forms examined, CYP3A was expressed in the highest amount and it was the only form whose content was correlated with total CYP450 content. Content of other forms was independent of total CYP450. We further determined the contribution of specific forms to the biotransformation of trichloroethylene as a model substrate. CYP2E1 was strongly correlated with chloral hydrate formation from trichloroethylene; CYP2B displayed the strongest correlation with trichloroethanol formation. These data describing the expression and distribution of these forms in human microsomes can be used to extrapolate in vitro derived metabolic rates for toxicologically important reactions, when form selectivity and specific activity are known. This approach may be applied to refine estimates of human interindividual differences in susceptibility for application in human health risk assessment. [Description provided by NIOSH]
• Subjects:
  Enzymes Hazardous Substances Occupational Health Risk Assessment Risk Factors Safety
• Keywords:
  Author Keywords: Risk Assessment Biotransformation Cytochrome P450 ELISA Human Variance In Vitro Studies Metabolic Rate Metabolism Microsomes Organs Oxidation Proteins Risk Analysis Risk Factors Sampling Sampling Methods Toxic Effects Toxins Uncertainty Factors

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• ISSN:
  0273-2300
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Ohio ; OSHA Region 5
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  DART - Division of Applied Research and Technology
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  200-209
• Volume:
  32
• Issue:
  2
• NIOSHTIC Number:
  nn:20020814
• Citation:
  Regul Toxicol Pharmacol 2000 Oct; 32(2):200-209
• Contact Point Address:
  U.S. Environmental Protection Agency, National Center for Environmental Assessment, MD-190, 26 W. Martin Luther King Drive, Cincinnati, OH 45268
• Email:
  Lipscomb.John@EPA.GOV
• CAS Registry Number:
  Trichloroethylene (CAS RN 79-01-6)
• Federal Fiscal Year:
  2001
• Peer Reviewed:
  True
• Source Full Name:
  Regulatory Toxicology and Pharmacology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:46f164541ff33d61a6fd3c26be14db78643b9e49adf71b065f96fa41ae986952de47c85e0eb8c0d4b8cc7a34a245f9e98b97249653efdb3b174630b00afe12d8
• Download URL:
  https://stacks.cdc.gov/view/cdc/198479/cdc_198479_DS1.pdf
• File Type:
  [PDF - 113.63 KB ]