Genetic polymorphisms of drug-metabolizing enzymes and anti-TB drug-induced hepatitis.

Abstract

AIMS:

Although some genetic risk factors have been reported for the development of hepatitis due to anti-TB drugs, an extensive candidate gene approach evaluating drug-metabolizing enzymes has not been attempted. This study aimed to investigate the association of genetic polymorphisms in drug-metabolizing enzymes with anti-TB drug-induced hepatitis.

MATERIALS & METHODS:

We compared genotype distributions of tagging SNPs in promoter, exons and haplotypes in seven drug-metabolizing enzyme genes (CYP2C9, CYP2C19, CYP2D6, CYP2E1, NAT2, UGT1A1 and UGT1A3) between 67 cases and 159 controls.

RESULTS:

Among four tagging SNPs of N-acetyltransferase 2 (NAT2), -9796T>A in promoter and R197Q were significantly associated (p = 0.0016 and p = 0.0007, respectively). NAT2 haplotype 2 [A-A-A-G] carrying A allele of -9796T>A and A allele of R197Q showed significant association (p = 0.0004). However, there was no significant association between genotypes of other enzyme-metabolizing genes and anti-TB drug-induced hepatitis. The constructs containing -9796A of NAT2 showed significantly lower luciferase activity (p < 0.01), suggesting decreased expression of NAT2. The variant alleles and haplotype 2 showed significantly higher peak serum levels of isoniazid, lower acetyl isoniazid:isoniazid ratio and lower isoniazid clearance compared with wild-types.

CONCLUSION:

These findings suggest that genetic variants in the promoter and exons of NAT2 increase the risk of anti-TB drug-induced hepatitis by modifying acetylation phenotypes and/or gene expression of NAT2, and there is no essential role for genetic mutation of the other metabolizing enzymes in the development of this adverse reaction.

• Authors: Sang-Heon Kim, Sang-Hoon Kim, Joon-Woo Bahn, Yoon-Keun Kim, Yoon-Seok Chang, Eun-Soon Shin, Youn-Seup Kim, Jae-Seuk Park, Bo-Hyung Kim, In-Jin Jang, Junghan Song, Seung-Hyun Kim, Hae-Sim Park, Kyung-Up Min, Young-Koo Jee
• Journal: Pharmacogenomics (Pharmacogenomics) Vol. 10 Issue 11 Pg. 1767-79 (Nov 2009) ISSN: 1744-8042 [Electronic] England
• PMID: 19891553 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antitubercular Agents
• Arylamine N-Acetyltransferase
• NAT2 protein, human
• Isoniazid

Topics

• Acetylation
• Antitubercular Agents (adverse effects)
• Arylamine N-Acetyltransferase (genetics)
• Chemical and Drug Induced Liver Injury (genetics)
• Haplotypes
• Humans
• Isoniazid (blood, metabolism)
• Polymorphism, Single Nucleotide