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Final Progress Reports: University of Washington: Fingerprinting of Cytochrome P-450 Profiles as Biomonitors of Chemical Exposure and Risk in Humans

Superfund Research Program

Fingerprinting of Cytochrome P-450 Profiles as Biomonitors of Chemical Exposure and Risk in Humans

Project Leader: Curtis J. Omiecinski
Grant Number: P42ES004696
Funding Period: 1995 - 2000

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Final Progress Reports

Year:   1999 

Project 4 will not be continuing in the new funding cycle. The summary provided reflects the final year's effort of this project. Dr. Omiecinski, together with his laboratory colleagues, Dr. Barbara Krovat and Julia Tracy, conducted a comprehensive analysis of cytochrome and microsomal epoxide hydrolase expression profiles in human peripheral lymphocytes from 10 individuals. Gene expression levels were established with a novel and highly sensitive quantitative-competitive RT-PCR assay, developed earlier in this research program. In the current investigation, it was determined that patterns of constitutive P450 and mEH expression profiles in lymphocytes were remarkably consistent among individuals; however, the patterns and expression levels differed significantly from those found in liver. Another objective of this research was to validate established human blood cell lines as potential models to study chemical induction of drug metabolizing enzymes. Human leukemia cell lines express major blood cell specific markers and are widely used models to study aspects of hematopoesis, cell differentiation and CYP expression and regulation. Therefore, the researchers compared constitutive P450 and mEH expression patterns in four different cell lines with those in fresh human lymphocytes, and tested these cell lines for their ability to respond to prototypical chemical inducers. Results from these studies indicated that the blood cells are only marginally responsiveness to inducer treatments. In summary, given the relatively low levels of both mRNA and protein expression in blood cells associated with a battery of selected drug metabolizing enzymes, project investigators conclude that the blood cell lines characterized in this study have only limited value with respect to modeling the basal or inducible gene expression character of biotransformation in the liver, or, in this sense as a suitable biomarker of assessing risk of chemical exposure in humans. However, the QC RT-PCR assay used in this study was demonstrated to be a powerful tool to characterize different cell types for their respective CYP gene expression patterns and induction behavior. Although the effectiveness of blood cells as models of liver expression is called into question by these studies, importantly, our data suggest that established human blood cell lines reflect the constitutive cytochrome and mEH expression status of primary blood lymphocytes and therefore are appropriate models for studying blood cell related xenobiotic metabolism.

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