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Department of Environmental Health [C. J. O., C. A. R., P. C.], School of Public Health and Community Medicine, SC-34, and Department of Medicine [C. A. R.], School of Medicine, ZA-66, University of Washington, Seattle, Washington 98195
The expression of cytochrome P450 genes directly within target cells is an important determinant of human susceptibility to cancers, birth defects, and other chemically initiated diseases. One pivotal gene, CYP1A1, codes for an inducible cytochrome P450 isozyme (P450IA1) responsible for the bioactivation of numerous carcinogenic polycyclic hydrocarbons and aromatic amines. In this study, we used the polymerase chain reaction (PCR) to amplify endogenous P450IA1 mRNA transcripts in a variety of human and rat tissues from different stages of development. The PCR approach greatly enhanced detection sensitivities over those previously achieved and permitted characterization of constitutive as well as induced P450IA1 mRNA expression patterns in specific cell types and organs and during early gestational stages. P450IA1 mRNAs are expressed constitutively in the rat as early as day 15 of fetal liver development and increased in level with increasing developmental age. Transplacental treatment of fetal rats with 3-methylcholanthrene resulted in marked increases in P450IA1 mRNA levels, and responsiveness to the inducer also increased in concordance with developmental age. Comparatively lower constitutive and induced levels of the mRNA were detected in rat lung and kidney, but no P450IA1 mRNA was detected in the rat testis. PCR results obtained from experiments with human tissue samples demonstrated the presence of P450IA1 transcripts in whole organs, in purified cell fractions (lymphocytes, macrophages), and in fetuses as early as day 45 of human gestation. Data from cell culture studies indicated markedly higher levels of P450IA1 PCR product in human pulmonary alveolar macrophages following treatment with the inducing agent ß-naphthoflavone. These results underscore the potential role of P450IA1 as a key determinant of individual susceptibility to tissuespecific and developmentally related cancers associated with certain environmental chemical exposures.
1 This research was supported by Grants GM-32281, ES-04978, and ES-04696 from the NIH and by a fellowship award to C. A. R. from the American Lung Association.
Received 1/26/90.
Revised 3/26/90.
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