The broad, long term objective is to provide a better understanding of mechanisms whereby foreign organic chemicals produce persistent birth defects in humans. It is expected that such an understanding will lead to a minimization of human birth defects, an enormous problem in modern society. Specifically, the research is designed to elucidate the mechanistic roles of individual embryonic P450 cytochromes (whose genes are expressed during organogenesis in human embryonic tissues) as determinants of the capacity of certain chemicals to produce dysmorphogenesis/embryotoxicity. Focus is on organogenesis because this is the period of gestation during which the conceptus reputedly is most sensitive to chemical insult. The research will focus on P450 isoforms expressed in three specific human embryonic tissues - brain, adrenal gland and liver. Focus on the former two is because of high importance as target sites for embryotoxic effects and on the liver because of background information and relatively high levels of certain isoforms. Expression and regulation of expression of CYP1B1 in these tissues will be given high priority because P4501B1 mRNA has been detected in each of the three tissues of interest, because 1B1 seems likely to play an important role in developmental processes, and because 1B1 can be profoundly regulated by both environmental chemicals (e.g., TCDD) and endogenous chemicals (e.g., cAMP). Next priority will be given to isoforms now also found to be expressed in human embryonic tissues. These are P450s 2E1, 3A7 and 1A1. 2E1 has been detected in human embryonic cephalic tissues, 3A7 is present in relatively high quantities in human embryonic liver, and 1A1 has been found in human embryonic liver and brain. Evidence for still other P450 isoforms in these tissues has been found and efforts will be made to identify and determine their roles as determinants of chemically induced embryotoxicity. The tools of modern molecular biology and biochemistry will be used to characterize these isoforms, particularly in terms of mechanisms of their regulation in embryonic tissues. A rodent whole embryo culture system will be utilized for examination of the mechanistic roles that individual P450 isoforms can play in the embryotoxic effects of specific chemicals. Results obtained should provide health professionals and regulatory agencies a more rational basis for advising women with respect to their exposures to drugs and environmental chemicals during pregnancy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004041-13
Application #
2872269
Study Section
Special Emphasis Panel (ZRG4-ALTX-2 (01))
Project Start
1986-04-01
Project End
2001-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
13
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Washington
Department
Pharmacology
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) 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
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

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