Sex, ethnicity, and slow acetylator profile are the major causes of hepatotoxicity induced by antituberculosis drugs

Chamorro, Julián G.; Castagnino, Jorge; Musella, Rosa M.; Nogueras, Mabel; Aranda, Federico; Frías, Ana; Visca, Mabel; Aidar, Omar; Perés, Silvia; Larrañaga, Gabriela de

doi:10.1111/jgh.12069

Cited by 57 publications

(53 citation statements)

References 28 publications

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“…NAT2 is one of the factors responsible for genetic predisposition to INH-induced hepatitis and NAT2 acetylating status is related to the patient's condition, sex and ethnic origin, so it may be regarded as important risk factor for the development of hepatotoxicity (Mahmoud et al 2012, Chamorro et al 2013.…”

Section: Association Among Clinical Factors Genotypes and Atd-inducementioning

confidence: 99%

“…The frontline drug, INH, has been extensively studied (Cheng et al 2013). In the human liver, INH is first acetylated by N-acetyltransferase 2 (NAT2) into acetylhydrazine, then oxidized into toxic intermediaries by cytochrome P450 2E1 (CYP2E1) (Huang et al 2003, Chamorro et al 2013). The toxic compounds produced are detoxified by further acetylation by NAT2 and by conjugation reactions catalyzed by glutathione S-transferase enzymes (GST).…”

Section: Introductionmentioning

confidence: 99%

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Polymorphisms in CYP2E1, GSTM1 and GSTT1 and anti-tuberculosis drug-induced hepatotoxicity

Brito

Possuelo

Valim

et al. 2014

An. Acad. Bras. Ciênc.

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Anti-tuberculosis drug-induced hepatitis (ATD-induced hepatitis) has been linked to polymorphisms in genes encoding drug metabolizing enzymes. N-acetyltransferase 2 (NAT2), cytochrome P450 2E1 (CYP2E1) and glutathione S-transferase (loci GSTM1 and GSTT1) are involved in the metabolism of isoniazid, the most toxic drug for the treatment of tuberculosis (TB). This study was designed to determine the frequency and to evaluate whether polymorphisms at CYP2E1, GSTM1 and GSTT1 genes are associated with drug response, as well as to identify clinical risk factors for ATD-induced hepatitis. A total of 245 Brazilian patients undergoing treatment for TB were genotyped using polymerase chain reaction and restriction fragment length polymorphism and sequencing methods. The frequencies of the CYP2E1 polymorphic alleles RsaI, PstI and DraI are 8%, 8.5% and 12%, respectively. GSTM1 and GSTT1 genes are deleted in 42.9% and 12.4% of the population, respectively. Fifteen patients (6.1%) developed hepatotoxicity. Clinical (HIV, female sex and extrapulmonary TB) and genetic characteristics (CYP2E1 without any mutations, having NAT2 slow acetylator profile) are at higher risk of developing ATD-induced hepatitis in this population. Genotyping for GSTM1 and GSTT1 showed no influence on drug response.

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Section: Association Among Clinical Factors Genotypes and Atd-inducementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Polymorphisms in CYP2E1, GSTM1 and GSTT1 and anti-tuberculosis drug-induced hepatotoxicity

Brito

Possuelo

Valim

et al. 2014

An. Acad. Bras. Ciênc.

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“…TB is a re-emerging infectious disease with a high level of hepatotoxicity (25.6%) in hospitalized TB patients in Argentina [19]. Therefore, the present survey investigated the environmental factors and pharmacogenetic variation involved in INH metabolism and evaluated their association with ATDH independently and/or through complex interactions between them in a sample of hospitalized TB patients in Buenos Aires.…”

Section: Introductionmentioning

confidence: 99%

“…Some studies of the pharmacogenetics of TB found an association between genetic variations in these enzymes and ATDH development [10,[19][20][21]. The NAT2 gene was studied widely, and several surveys found an association between the slow acetylator phenotype and ATDH development [10,19,20,22].…”

Section: Introductionmentioning

confidence: 99%

“…The NAT2 gene was studied widely, and several surveys found an association between the slow acetylator phenotype and ATDH development [10,19,20,22]. The single nucleotide polymorphism (SNP) C-1053T in the CYP2E1 gene, also called c1/c2 or the RsaI variant, is one of the most studied genetic variants that is also associated with ATDH susceptibility [21,23].…”

Section: Introductionmentioning

confidence: 99%

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Effect of gene–gene and gene–environment interactions associated with antituberculosis drug-induced hepatotoxicity

Chamorro

Castagnino

Aidar

et al. 2017

Pharmacogenetics and Genomics

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a Objectives This study evaluated the association between environmental factors and genetic variations in enzymes that metabolize antituberculosis (anti-TB) drugs [arylamine N-acetyltransferase 2, cytochrome P450 2E1 (CYP2E1), glutathione S-transferase theta 1 (GSTT1), and glutathione S-transferase mu 1] with antituberculosis drug-induced hepatotoxicity (ATDH). We also investigated the potential gene-gene and gene-environment interactions as well as their association with ATDH development in a population of hospitalized TB patients from Buenos Aires.Patients and methods We investigated 364 TB patients who received anti-TB drugs. Physicians collected demographic and clinical data to identify environmental risk factors for ATDH development. Polymorphisms were detected using gene sequencing, PCR, and PCR-restriction fragment length polymorphisms. A binary logistic regression analysis was carried out to compare the results of TB patients with and without the development of hepatotoxicity. The multifactor dimensionality reduction method was used to examine genetic and environmental interactions in association with ATDH.Results This study suggests that the slow acetylator profile [odds ratio (OR): 3.02; 95% confidence interval (CI): 1.82-5.00; P < 0.001], genotypes carrying the c2 variant (OR: 2.16; 95% CI: 1.33-3.51; P = 0.002) or the A4 variant of CYP2E1 (OR: 2.13; 95% CI: 1.06-4.29; P = 0.050), and female sex (OR: 1.94; 95% CI: 1.20-3.14; P = 0.006) were independent predictor variables for ATDH. Patients carrying the slow acetylator profile and the c2 variant showed an increased risk (OR: 7.068; 95% CI: 3.34-14.95; P < 0.001).We also identified a synergic interaction (epistasis) between GSTT1 and CYP2E1 associated with an increased risk for ATDH. A meaningful gene-environment interaction was associated with an increased risk of ATDH [testing balance accuracy = 0.675 (P = 0.001) and cross-validation consistency = 10/10].Conclusion ATDH is a severe and prevalent adverse drug reaction and leads to drug discontinuation in 11% of TB patients. Our study created a prediction model that properly classified the 67.5% of TB patients in their risk of developing ATDH. The considerable number of TB patients in our country supports the use of pharmacogenetic testing and a comprehensive clinical history to identify patients with a high risk of suffering hepatotoxicity. Pharmacogenetics and Genomics 00:000-000

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Drug‐Metabolizing Enzymes and Drug Toxicity

2021

Transporters and Drug‐Metabolizing Enzymes in Drug Toxicity

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Sex, ethnicity, and slow acetylator profile are the major causes of hepatotoxicity induced by antituberculosis drugs

Cited by 57 publications

References 28 publications

Polymorphisms in CYP2E1, GSTM1 and GSTT1 and anti-tuberculosis drug-induced hepatotoxicity

Polymorphisms in CYP2E1, GSTM1 and GSTT1 and anti-tuberculosis drug-induced hepatotoxicity

Effect of gene–gene and gene–environment interactions associated with antituberculosis drug-induced hepatotoxicity

Drug‐Metabolizing Enzymes and Drug Toxicity

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