Association of slow N-acetyltransferase 2 profile and anti-TB drug-induced hepatotoxicity in patients from Southern Brazil.
OBJECTIVE
To determine the frequency of N-acetyltransferase 2 (NAT2) polymorphisms, the NAT2 acetylation profile and its relation to the incidence of gastrointestinal adverse drug reactions (ADRs), anti-tuberculosis (TB) drug-induced hepatotoxicity, and the clinical risk factors for hepatotoxicity in a population from Brazil.


METHODS
Two hundred and fifty-four Brazilian TB patients using isoniazid (INH), rifampicin (RMP), and pirazinamide (PZA) were tested in a prospective cohort study. NAT2 genotyping was performed by direct PCR sequencing. The association between gastrointestinal ADRs/hepatotoxicity and the NAT2 profile genotype was evaluated by univariate analysis and multiple logistic regression.


RESULTS
Of the 254 patients analyzed, 69 (27.2%) were slow acetylators and 185 (72.8%) were fast acetylators. Sixty-five (25.6%) patients were human immunodeficiency virus (HIV)-positive. Thirty-three (13%) and 14 (5.5%) patients developed gastrointestinal ADR and hepatotoxicity, respectively. Of the 14 hepatotoxicity patients, nine (64.3%) were slow acetylators and five (35.7%) were fast acetylators. Sex, age, presence of hepatitis C virus, alcohol abuse, and baseline aminotransferases were not found to be risk factors for hepatotoxicity. However, logistic regression analysis revealed that slow acetylator status and the presence of HIV (p < 0.05) were independent risk factors for hepatotoxicity.


CONCLUSIONS
Our findings show that HIV-positive patients that have the slow acetylation profile are significantly associated with a higher risk of developing hepatotoxicity due to anti-TB drugs.
Possuelo
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LG
Centro de Desenvolvimento Científico e Tecnológico da Fundação Estadual de Produção e Pesquisa em Saúde, 5400 Avenida Ipiranga, Porto Alegre, RS 90610-000, Brazil.
Castelan
J A
JA
de Brito
T C
TC
Ribeiro
A W
AW
Cafrune
P I
PI
Picon
P D
PD
Santos
A R
AR
Teixeira
R L F
RL
Gregianini
T S
TS
Hutz
M H
MH
Rossetti
M L R
ML
Zaha
A
A
D000107:Acetylation; D000995:Antitubercular Agents / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D001938:Brazil; D015331:Cohort Studies; D017931:DNA Primers; D008099:Liver / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D014376:Tuberculosis / Q000188:drug therapy*
D000995:Antitubercular Agents; D017931:DNA Primers; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human