The long-range goal of the proposed research is to better understand mechanisms whereby foreign organic chemicals produce malformations and other forms of toxicity in developing embryos. Because recent research as indicated that embryonic enzyme systems can catalyze conversion of environmental chemicals to quantities of reactive intermediates sufficient to elicit readily observalbe gross malformations, an integral aspect of the outlined investigation is the study of specific embryonic bioactivating enzyme systems. Preliminary studies suggest that at least two embryonic P-45's (P-450c and P-450p) can effect highly significant bioactivating activity. It is the intention of this proposal to focus on these two hemoproteins in terms of their bioactivating potential in embryonic tissues. In order to avoid the influence of potentially confounding maternal factors, the whole embryo culture system has been chosen for study. The two hemoproteins will be analyzed with a combination of substrate probe analyses, inhibitor probe analyses and immunoquantitation. Investigations of the models of regulation of these embryonic hemoproteins will be initiated. The feasibiity of the approaches has been demonstrated in preliminary experiments. Comparisons of rodent embryos with prenatal tissues from humans and subhuman primates will also be made. Results obtained from the research should provide health professionals a more rational basis for providing advice to pregnant women with respect to their exposure to foreign organic chemicals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES004041-01
Application #
3251897
Study Section
Toxicology Study Section (TOX)
Project Start
1986-04-01
Project End
1991-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Trofimova-Griffin, Marina E; Juchau, Mont R (2002) Developmental expression of cytochrome CYP26B1 (P450RAI-2) in human cephalic tissues. Brain Res Dev Brain Res 136:175-8
Person, R E; Chen, H; Fantel, A G et al. (2000) Enzymic catalysis of the accumulation of acetaldehyde from ethanol in human prenatal cephalic tissues: evaluation of the relative contributions of CYP2E1, alcohol dehydrogenase, and catalase/peroxidases. Alcohol Clin Exp Res 24:1433-42
Trofimova-Griffin, M E; Brzezinski, M R; Juchau, M R (2000) Patterns of CYP26 expression in human prenatal cephalic and hepatic tissues indicate an important role during early brain development. Brain Res Dev Brain Res 120:16-Jul
Khalighi, M; Brzezinski, M R; Chen, H et al. (1999) Inhibition of human prenatal biosynthesis of all-trans-retinoic acid by ethanol, ethanol metabolites, and products of lipid peroxidation reactions: a possible role for CYP2E1. Biochem Pharmacol 57:811-21
Brzezinski, M R; Boutelet-Bochan, H; Person, R E et al. (1999) Catalytic activity and quantitation of cytochrome P-450 2E1 in prenatal human brain. J Pharmacol Exp Ther 289:1648-53
Chen, H; Brzezinski, M R; Fantel, A G et al. (1999) Catalysis of drug oxidation during embryogenesis in human hepatic tissues using imipramine as a model substrate. Drug Metab Dispos 27:1306-8
Chen, H; Juchau, M R (1998) Inhibition of embryonic retinoic acid synthesis by aldehydes of lipid peroxidation and prevention of inhibition by reduced glutathione and glutathione S-transferases. Free Radic Biol Med 24:408-17
Trofimova-Griffin, M E; Juchau, M R (1998) Expression of cytochrome P450RAI (CYP26) in human fetal hepatic and cephalic tissues. Biochem Biophys Res Commun 252:487-91
Chen, H; Juchau, M R (1998) Recombinant human glutathione S-transferases catalyse enzymic isomerization of 13-cis-retinoic acid to all-trans-retinoic acid in vitro. Biochem J 336 ( Pt 1):223-6
Chen, H; Juchau, M R (1998) Biotransformation of 13-cis- and 9-cis-retinoic acid to all-trans-retinoic acid in rat conceptal homogenates. Evidence for catalysis by a conceptal isomerase. Drug Metab Dispos 26:222-8

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