Genetic Variations of
            <i>NAT2</i>
            and
            <i>CYP2E1</i>
            and Isoniazid Hepatotoxicity in a Diverse Population

Yamada, So; Tang, Mila; Richardson, Kathryn; Halaschek-Wiener, Julius; Chan, Matthew; Cook, Victoria; FitzGerald, J. Mark; Elwood, R. Kevin; Brooks‐Wilson, Angela; Marra, Fawziah

doi:10.2217/pgs.09.66

Cited by 67 publications

(49 citation statements)

References 47 publications

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“…CES4 CES1 and CES4 50 We have assessed the effect of genetic variation in three novel candidate genes for hepatotoxicity, CES1, CES2 and CES4, by systematically cataloguing the variants present in subjects with and without hepatotoxicity, and conducting association tests of SNPs and haplotypes. We found no evidence for association of genetic variation in CES2 with INH-induced hepatotoxicity.…”

Section: Ces1mentioning

confidence: 99%

Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity

et al. 2010

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Treatment of latent tuberculosis infection (LTBI) generally includes isoniazid (INH), a drug that can cause serious hepatotoxicity. Carboxylesterases (CES) are important in the metabolism of a variety of substrates, including xenobiotics. We hypothesized that genetic variation in CES genes expressed in the liver could affect INH-induced hepatotoxicity. Three CES genes are known to be expressed in human liver: CES1, CES2 and CES4. Our aim was to systematically characterize genetic variation in these novel candidate genes and test whether it is associated with this adverse drug reaction. As part of a pilot study, 170 subjects with LTBI who received only INH were recruited, including 23 cases with hepatotoxicity and 147 controls. All exons and the promoters of CES1, CES2 and CES4 were bidirectionally sequenced. A large polymorphic deletion was found to encompass exons 2 to 6 of CES4. No significant association was found. Eleven single-nucleotide polymorphisms (SNPs) in CES1 were in high linkage disequilibrium with each other. One of these SNPs, C(À2)G, alters the translation initiation sequence of CES1 and represents a candidate functional polymorphism. Replication of this possible association in a larger sample set and functional studies will be necessary to determine if this CES1 variant has a role in INH-induced hepatotoxicity.

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Section: Ces1mentioning

confidence: 99%

Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity

et al. 2010

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“…The major alleles groups associated with decreased enzyme activity due to amino acid changes and, therefore, a slow acetylator phenotype, are NAT-2*5, NAT-2*6, NAT-2*7 and NAT-2*14 [4]; in several surveys homozygous wild type alleles at all four loci that have no variations are called RA and are represented as NAT-2*4 [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

“…The SA acetylation status has been associated with Isoniazid (INH)-induced hepatitis in Asian populations [1,5]. INH, a substrate of NAT-2, is a first-line drug used in tuberculosis (TB) treatment, and it is considered to be responsible for adverse drug reactions that lead to hepatotoxicity [6,8,9].…”

Section: Introductionmentioning

confidence: 99%

“…INH, a substrate of NAT-2, is a first-line drug used in tuberculosis (TB) treatment, and it is considered to be responsible for adverse drug reactions that lead to hepatotoxicity [6,8,9]. Although an association between NAT-2 acetylation polymorphism and INH-induced hepatotoxicity has been reported by several studies, considerable controversies remain as a consequence of the wide variability in the results of these studies [5][6][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…In patients, it can result in liver failure and death. In public health, TB is associated with a prolonged hospital treatment and the risk of developing bacterial resistance, implying an increase in health costs [5,6].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The distribution of allelic and genotypic frequencies of N-Acetyltransferase-2 variants in an Argentine population

Chamorro

Castagnino

Musella

et al. 2012

J Infect Dev Ctries

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Introduction: Arylamine N-acetyltransferase-2 (NAT-2) is a key human enzyme in drug detoxification and elimination. Mutations in NAT-2 affect the activity of anti-tuberculosis drugs and result in three different phenotypes: rapid (RA), intermediate (IA) and slow acetylators (SA). Methodology: The allelic, genotypic and phenotypic frequencies of NAT-2 were studied in 185 patients from Buenos Aires by restriction fragment length polymorphism. Results: The following allele frequencies were obtained: *4 = 29.9%, *5 = 37.0, *6 = 25.6%, *7 = 8% and *14 = 1.3%. With regard to the phenotype, we observed that 53.6% of the population was SA, 35.7% was IA and 10.7% was RA. Conclusion: A high prevalence of SA might have an impact on anti-TB drug-induced hepatotoxicity.

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Pharmacogenetics in Drug Metabolism: Role of Phase I Enzymes

Dolžan

2012

Pharmacogenetics and Individualized Therapy

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Genetic Variations of NAT2 and CYP2E1 and Isoniazid Hepatotoxicity in a Diverse Population

Cited by 67 publications

References 47 publications

Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity

Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity

The distribution of allelic and genotypic frequencies of N-Acetyltransferase-2 variants in an Argentine population

Pharmacogenetics in Drug Metabolism: Role of Phase I Enzymes

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