N-acetyltransferase: the practical consequences of polymorphic activity in man

Area of Science:

• Pharmacogenetics
• Drug Metabolism
• Toxicology

Background:

• The "slow acetylator" phenotype is associated with an elevated risk of adverse drug reactions.
• Specific examples include hepatotoxicity and neuropathy with isoniazid, lupus-like symptoms with procainamide, and hypersensitivity to sulfonamides.
• Slow acetylators exposed to arylamines have a higher likelihood of developing bladder cancer, while rapid acetylators may face a slight risk of pancreatic tumors.

Purpose of the Study:

• To review and synthesize existing evidence on the clinical implications of N-acetylation polymorphism.
• To investigate the association between N-acetylation status and various disease states.
• To clarify the role of N-acetylation in drug efficacy and toxicity.

Main Methods:

• Review of numerous studies examining the "slow acetylator" phenotype and its link to adverse drug reactions.
• Analysis of patient groups with diverse disease states to identify associations with N-acetylation differences.
• Evaluation of conflicting data and calculated risk factors from existing research.

Main Results:

• Consistent evidence links the slow acetylator phenotype to increased risk of specific drug toxicities and carcinogen-induced cancers.
• Data on other therapeutic agents where N-acetylation plays a minor role remains inconclusive regarding clinical impact.
• Studies examining disease associations have yielded equivocal and often contradictory results.

Conclusions:

• The slow acetylator phenotype is a significant risk factor for certain adverse drug reactions and cancers.
• The clinical relevance of N-acetylation polymorphism in other contexts is still under investigation.
• Other unappreciated factors likely contribute to inter-individual variability in drug response and disease susceptibility.