Application of pharmacogenomics in drug discovery and development: correlations between transcriptional modulation and preclinical safety observations.
An integrated systems biology approach of measuring mRNA, protein and enzyme activity, was used to determine the molecular mechanisms responsible for reductions in thyroid hormone levels observed in rats given 1000 mg/kg/day of a nonsteroidal progesterone agonist (NSP). The effect of NSP on drug metabolizing enzyme (DME) expression was determined in livers from treated and vehicle control rats. In treated males, CYP1A1, CYP2B1, CYP2B2, CYP2C12, CYP3A1 and UGT1A mRNAs increased by 2.2, 31.0, 9.4, 13.0, 6.4 and 2.3 fold, while CYP2C11 and CYP3A2 levels decreased by 4.8 and 15.0 fold respectively. CYP1A, CYP2B and UGT1A enzyme activities increased by 2.9, 6.2 and 1.4 fold while CYP2C and CYP3A activities decreased by 2.2 and 1.8 fold respectively. CYP2B and CYP2C proteins increased by 2.1 and 1.3 fold but CYP2C11, the male-specific isozyme, and CYP3A protein decreased by 2.0 and 1.4 fold respectively. In treated females, CYP1A, CYP2B, CYP2C, CYP3A and UGT activities increased by 1.9, 12.0, 23.0, 13.0 and 2.2 fold respectively; with corresponding increases in mRNA ranging from 1.5 to 783 fold. CYP2B, CYP2C and CYP3A proteins increased by 3.6, 2.2 and 6.4 fold respectively, but CYP2C11 remained unchanged. These data suggest that NSP modulates the transcriptional regulation DME in rats and could account for the observed reductions in thyroid hormones, since UGT conjugation is the main pathway of thyroid hormone elimination in rats. These data also show gender and isozyme-specific regulation of some genes, thus demonstrating the value of an integrated approach in determining the contribution of individual genes in drug safety and metabolism observations.
Biotransformation Division, Drug Safety and Metabolism, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. yengil@wyeth.com
Lilian G
LG
Yengi
Qian
Q
Xiang
Li
L
Shen
Appavu
A
Chandrasekaran
John
J
Kao
JoAnn
J
Scatina
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010597:Pharmacogenetics / Q000379:methods*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011980:Receptors, Progesterone / Q000819:agonists; D012737:Sex Factors; D049490:Systems Biology / Q000379:methods*; D013963:Thyroid Hormones / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D012333:RNA, Messenger; D011980:Receptors, Progesterone; D013963:Thyroid Hormones; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase