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© 1996 Oxford University Press

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Drug Metabolic Enzymes in Developmental Toxicology1

MARK STEVEN MILLER*, MONT R. JUCHAU{dagger}, F. PETER GUENGERICH{ddagger}, DANIEL W. NEBERT§ and JUDY L. RAUCY

*Department of Cancer Biology and Physiology & Pharmacology, Bowman Gray School of Medicine, Comprehensive Cancer Center of Wake Forest University Winston-Salem, North Carolina 271157 {dagger}Department of Pharmacology, University of Washington School of Medicine Seattle, Washington 98195 {ddagger}Department of Biochemistry, Vanderbilt University Nashville, Tennessee 37232 §Department of Environmental Health, University of Cincinnati Cincinnati, Ohio 45267 ¶The Agouron Institute La Jolla, California 92037

Received September 13, 1996; accepted September 17, 1996

Although much is known about the metabolism of environmental toxicants in adult organisms, little information exists on the role of cytochrome P450 (CYP) enzymes during development. The developing organism is remarkably dynamic, presenting a constantly changing metabolic profile as various enzyme systems are activated or repressed. This may explain the markedly different sensitivities to various toxicants that are exhibited throughout the developmental period. The application of molecular biological methods has provided important information on the roles of these enzymes in modulating the response of the developing organism to toxicological exposures. The first talk will focus on the identification and role of CYPs during early organogenesis, particularly on how these enzymes influence the response of the conceptus and early embryo to toxic chemicals. The second presentation will discuss the identification of CYPs expressed during human development, as many of the enzymes present in adults are not expressed in the fetus. The third speaker will discuss the developmental consequences of loss of expression of particular metabolic enzymes, focusing on recent studies employing knockout mice to examine the role of drug metabolic enzymes during development. The last two talks will discuss some of the short- and long-term consequences of in utero exposures to toxic chemicals and the role of CYP in modulating the toxic response of the developing organism. The first of these will focus on the role of CYP2E1 in human fetuses during late gestation and the response of this enzyme to inducing agents such as alcohol. The last talk will discuss the role of CYP1A1 in the activation of the Ki-ras oncogene following in utero exposure to carcinogens as a mechanism for lung tumor formation in a pharmacogenetic mouse model.


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