Free Content N-acetyl transferase 2 and cytochrome P450 2E1 genes and isoniazid-induced hepatotoxicity in Brazilian patients

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Abstract:

SETTING: Isoniazid (INH) is related to the development of hepatotoxicity in some patients.

OBJECTIVE: To investigate the role of N-acetyl transferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) in the hepatotoxicity of patients treated with INH in an Amazonian Brazilian population.

DESIGN: Patients undergoing anti-tuberculosis treatment were investigated. Hepatotoxicity was defined as an increase of more than three times the upper limit of normal in serum alanine aminotransferase levels after treatment. NAT2 genotypes were identified by sequencing, whereas CYP2E1 alleles were detected using polymerase chain reaction based methods.

RESULTS: Of the 270 individuals included in the study, 18 (6.7%) developed drug-related hepatotoxicity. A high association was found between slow acetylators and hepatotoxicity, particularly with regard to allele *5. The adjusted risk of developing hepatotoxicity was significant in individuals carrying two slow acetylation alleles (P = 0.036, OR 3.05, 95%CI 1.07–8.64). In all of the CYP2E1 markers examined, wild homozygous genotypes were more prevalent in subjects with hepatotoxicity than in controls; however, the difference was not statistically significant. Joint evaluation of the genes revealed a high risk of developing hepatotoxicity in slow acetylators with CYP2E1 wild alleles (adjusted OR 4.26; 95%CI 1.47–12.37, P = 0.008).

CONCLUSIONS: Large-scale screening for NAT2 and CYP2E1 genotypes can prove useful in predicting the risk of adverse effects.

Keywords: adverse effects; pharmacogenetics; treatment; tuberculosis

Document Type: Research Article

DOI: http://dx.doi.org/10.5588/ijtld.12.0645

Affiliations: 1: Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belem, Para, Brazil 2: Departamento de Estatística, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil 3: Hospital João de Barros Barreto, Universidade Federal do Pará, Belem, Para, Brazil 4: Laboratório de Virologia Universidade Federal do Para, Belem, Para, Brazil 5: Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

Publication date: April 1, 2013

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  • The International Journal of Tuberculosis and Lung Disease publishes articles on all aspects of lung health, including public health-related issues such as training programmes, cost-benefit analysis, legislation, epidemiology, intervention studies and health systems research. The IJTLD is dedicated to the continuing education of physicians and health personnel and the dissemination of information on tuberculosis and lung health world-wide.

    Certain IJTLD articles are selected for translation into French, Spanish, Chinese or Russian. They are available on the Union website

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