DRUG METABOLIC ENZYMES IN DEVELOPMENTAL TOXICOLOGY

Although much is known about the metabolism of environmental toxicants in adult organisms, little information exists on the role of cytochro me P450 (CYP) enzymes during development, The developing organism is r emarkably 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 ex hibited throughout the developmental period, The application of molecu lar biological methods has provided important information on the roles of these enzymes in modulating the response of the developing organis m to toxicological exposures. The first talk will focus on the identif ication and role of CYPs during early organogenesis, particularly on h ow these enzymes influence the response of the conceptus and early emb ryo to toxic chemicals. The second presentation will discuss the ident ification of CYPs expressed during human development, as many of the e nzymes present in adults are not expressed in the fetus, The third spe aker 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 de velopment. The last two talks will discuss some of the short- and long -term consequences of in utero exposures to toxic chemicals and the ro le 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 agen ts such as alcohol, The last talk will discuss the role of CYP1A1 in t he activation of the Ki-ras oncogene following in utero exposure to ca rcinogens as a mechanism for lung tumor formation in a pharmacogenetic mouse model, (C) 1996 Society of Toxicology.