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Influence of polymorphic N-acetyltransferases on non-malignant spontaneous disorders and on response to drugs

J M Ladero1

  • 1Gastroenterology Service (Liver Unit), Hospital Clínico San Carlos. Complutense University, Madrid. Spain. jladero.hcsc@salud.madrid.org

Current Drug Metabolism
|August 6, 2008
PubMed

Insights

Polymorphic N-acetyl transferases (NAT) genes, particularly NAT2, may act as low-penetrance risk genes for certain diseases. While some conditions are ruled out, further research is needed for others like rheumatoid arthritis and Parkinson's disease.

Area of Science:

  • Pharmacogenetics
  • Toxicology
  • Disease Pathogenesis

Background:

  • Polymorphic N-acetyl transferases (NAT) 1 and 2 enzymes are crucial for detoxifying environmental chemicals like arylamines and hydralazines.
  • These chemicals are implicated in the pathogenesis of various disorders, including malignancies and degenerative diseases, potentially influenced by polygenic predisposition.
  • Polymorphic NAT genes, especially NAT2, are considered potential low-penetrance risk genes for these conditions.

Purpose of the Study:

  • To review the current evidence on the association between NAT gene polymorphisms and the risk of developing spontaneous disorders.
  • To identify diseases where a link with NAT2 polymorphism is inconclusive and requires further investigation.
  • To highlight the role of NAT2 polymorphism in drug-induced side effects.

Main Methods:

  • Literature review and synthesis of existing research findings.
  • Analysis of studies investigating the association between NAT gene polymorphisms and various diseases.
  • Evaluation of evidence for drug-induced side effects related to NAT2 metabolic status.

Main Results:

  • A definitive association between NAT gene polymorphisms and systemic lupus erythematosus, inflammatory bowel disease, and endometriosis has been ruled out.
  • Inconclusive but suggestive evidence exists for a possible relation between NAT2 polymorphism and rheumatoid arthritis, Parkinson's disease, Alzheimer's disease, Behçet's disease, and periodontal diseases.
  • NAT2 slow metabolizers exhibit increased susceptibility to adverse effects from drugs like hydralazine, procainamide, sulphasalazine, and sulfonamides.

Conclusions:

  • Further well-designed, large-scale studies are necessary to clarify the role of NAT2 polymorphism in the pathogenesis of several complex diseases.
  • The current evidence does not support a significant risk association for certain autoimmune and inflammatory conditions.
  • Understanding NAT2 genotype is important for predicting drug toxicity and managing patient safety.

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