Molecular basis for differences in susceptibility to toxicants: introduction

Area of Science:

• Toxicology
• Pharmacogenetics
• Molecular Biology

Background:

• Toxicant susceptibility is influenced by metabolic differences.
• Understanding the molecular basis of these differences has advanced significantly.
• Genetic polymorphisms in drug-metabolizing enzymes are increasingly understood.

Purpose of the Study:

• To review the current understanding of factors controlling drug-metabolizing enzyme expression and regulation.
• To highlight the molecular basis of common drug metabolism polymorphisms.
• To discuss the implications for understanding toxicant susceptibility.

Main Methods:

• Review of recent research on drug metabolism and genetic polymorphisms.
• Elucidation of molecular mechanisms for enzyme regulation and expression.
• Analysis of genetic variations in enzymes like CYP2D6, NAT2, and epoxide hydrolase.

Main Results:

• The molecular basis for common polymorphisms (e.g., CYP2D6, NAT2) is now known.
• Regulatory control of inducible enzymes (e.g., CYP1A1) is better understood.
• Genetic differences in enzymes like epoxide hydrolase explain previously idiosyncratic reactions.

Conclusions:

• The concept of idiosyncrasy in toxicant reactions is becoming obsolete.
• Applying knowledge of metabolic differences is key to identifying at-risk populations.
• Further research is needed on tissue-specific expression, species differences, and non-metabolic factors influencing susceptibility.