Increased risk of antituberculosis drug-induced hepatotoxicity in individuals with glutathione S-transferase M1 'null' mutation.
BACKGROUND
Pathogenesis and genetic factors influencing predisposition to antituberculosis drug (ATD)-induced hepatotoxicity are not clear. Polymorphism at the genetic locus of a drug and xenobiotic compound metabolizing enzyme, N-acetyltransferase type 2 (NAT2), is reported to be associated with the excess generation of toxic reactive metabolites. Polymorphisms at the glutathione S-transferase (GST) loci (GSTM1 and GSTT1) are involved in the detoxification of these toxic metabolites in the human body to a lesser extent. We have examined whether polymorphisms at these loci are associated with the risk of ATD-induced hepatotoxicity.


METHODS
In this case-control study, 33 pulmonary tuberculosis patients with ATD-induced hepatotoxicity and 33 pulmonary tuberculosis patients receiving ATD drugs without any evidence of hepatotoxicity were considered as cases and controls, respectively. Point mutations at NAT2 and homozygous 'null' mutations at GSTM1 and GSTT1 genes were looked into genomic DNA, isolated from peripheral blood mononuclear cells by using polymerase chain reaction (PCR).


RESULTS
The frequency of homozygous 'null' mutation at the GSTM1 gene was significantly higher among cases (n = 17, 52%) than controls (n = 8, 24%) (P < 0.05, relative risk 2.13, 95% CI: 1.25-3.10). Frequencies of mutations at GSTT1 and NAT2 genes did not differ significantly between cases and controls.


CONCLUSIONS
Homozygous 'null' mutation at the GSTM1 gene might predispose an individual to ATD-induced hepatotoxicity.
Roy
B
B
Anthropology and Human Genetics Unit, Indian Statistical Institute, Calcutta, India. broyisi@hotmail.com
Chowdhury
A
A
Kundu
S
S
Santra
A
A
Dey
B
B
Chakraborty
M
M
Majumder
P P
PP
D000293:Adolescent; D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D004252:DNA Mutational Analysis; D004359:Drug Therapy, Combination; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics; D012307:Risk Factors; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000201:enzymology
D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; D005982:Glutathione Transferase; C478900:NAT2 protein, human; C413545:glutathione S-transferase T1