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Application of pharmacogenomics in drug discovery and development: correlations between transcriptional modulation

Lilian G Yengi1, Qian Xiang, Li Shen

  • 1Biotransformation Division, Drug Safety and Metabolism, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. yengil@wyeth.com

Drug Metabolism Letters
|April 10, 2009
PubMed

Insights

A nonsteroidal progesterone agonist (NSP) alters drug metabolizing enzyme (DME) expression in rats, impacting thyroid hormone levels. This study reveals NSP

Area of Science:

  • Pharmacology
  • Toxicology
  • Systems Biology

Background:

  • Thyroid hormone levels can be affected by xenobiotics.
  • Drug metabolizing enzymes (DMEs) play a crucial role in hormone metabolism and elimination.
  • Understanding the molecular mechanisms behind xenobiotic-induced hormonal changes is vital for drug safety assessment.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying thyroid hormone reduction in rats treated with a nonsteroidal progesterone agonist (NSP).
  • To determine the effect of NSP on drug metabolizing enzyme (DME) expression and activity in a gender-specific manner.

Main Methods:

  • An integrated systems biology approach was employed, measuring mRNA, protein, and enzyme activity.
  • Liver samples from male and female rats treated with NSP and vehicle controls were analyzed.
  • Quantitative analysis of specific CYP (cytochrome P450) and UGT (uridine 5'-diphospho-glucuronosyltransferase) isoforms was performed.

Main Results:

  • NSP significantly altered the expression and activity of multiple DMEs (CYP1A, CYP2B, CYP2C, CYP3A, UGT1A) in a gender- and isozyme-specific manner.
  • In males, several DME mRNAs and activities increased, while CYP2C11 and CYP3A2 decreased significantly.
  • In females, most DME activities and proteins increased, with substantial mRNA upregulation for some isoforms.

Conclusions:

  • NSP modulates the transcriptional regulation of DMEs in rats, potentially explaining the observed reduction in thyroid hormone levels.
  • UGT conjugation is identified as a primary pathway for thyroid hormone elimination in rats.
  • The study highlights the importance of an integrated, gender-specific approach in evaluating drug safety and metabolism.

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