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NAT2 and CYP2E1 polymorphisms associated with antituberculosis drug-induced hepatotoxicity in Chinese patients

Hui-Ru An1, Xue-Qiong Wu, Zhong-Yuan Wang

  • 1Institute of Tuberculosis Research, 309th Hospital of Chinese People's Liberation Army, Beijing, China.

Clinical and Experimental Pharmacology & Physiology
|April 18, 2012
PubMed

Insights

Genetic variations in N-acetyltransferase 2 (NAT2) slow acetylator genotypes, particularly NAT2*6A/7B and NAT2*6A/6A, increase susceptibility to anti-TB drug-induced hepatotoxicity. Combining these with CYP2E1 C1/C1 genotype further elevates the risk.

Area of Science:

  • Pharmacogenomics
  • Hepatology
  • Infectious Diseases

Background:

  • Antituberculosis (anti-TB) drug-induced hepatotoxicity is a significant clinical concern.
  • Isoniazid metabolism involves key enzymes N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1).
  • Genetic variations in these enzymes may influence individual susceptibility to drug-induced liver injury.

Purpose of the Study:

  • To investigate the association between genetic polymorphisms of NAT2 and CYP2E1 and anti-TB drug-induced hepatotoxicity.
  • To identify specific genotypes that confer increased risk for hepatotoxicity in tuberculosis patients.

Main Methods:

  • Polymerase chain reaction direct sequencing was used to analyze NAT2 and CYP2E1 gene polymorphisms.
  • Genotyping was performed on tuberculosis patients with (n=101) and without (n=107) anti-TB drug-induced hepatotoxicity.
  • Statistical analysis was conducted to determine the association between genotypes and hepatotoxicity.

Main Results:

  • Specific NAT2 alleles (282TT, 590AA, 857GA) were linked to increased susceptibility to hepatotoxicity.
  • Slow acetylator NAT2 genotypes (NAT2*6A/7B, NAT2*6A/6A) were significant risk factors (OR 9.57, P < 0.001; OR 5.24, P = 0.02).
  • The CYP2E1 genotype alone was not associated, but its C1/C1 genotype combined with slow acetylator NAT2 genotypes significantly increased hepatotoxicity risk (OR 5.33, P = 0.003).

Conclusions:

  • Slow acetylator NAT2 genotypes (NAT2*6A/7B, NAT2*6A/6A), particularly when combined with the CYP2E1 C1/C1 genotype, are implicated in the pathogenesis of anti-TB drug-induced hepatotoxicity.
  • Altered isoniazid metabolism via NAT2 and CYP2E1 may lead to the production of hepatotoxic intermediates.
  • These findings highlight the role of pharmacogenetics in predicting and understanding anti-TB drug-induced liver injury.

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