Acetylator phenotype and genotype in patients infected with HIV: discordance between methods for phenotype determination and genotype

O’Neil, William M.; Drobitch, Robert K.; MacArthur, Rodger D.; Farrough, Marti J.; Doll, Mark A.; Fretland, Adrian J.; Hein, David W.; Crane, Lawrence R.; Svensson, Craig K.

doi:10.1097/00008571-200003000-00009

Cited by 50 publications

(41 citation statements)

References 26 publications

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“…Genetic and/or environmental effects on a number of enzyme systems (e.g., cytochrome P450, xanthine oxidase, NAT1) may affect metabolite levels used to assess phenotype. Other potential artifacts in the use of caffeine to determine acetylation phenotype also have been reported (Lorenzo and Reidenberg, 1989;Cribb et al, 1994;O'Neil et al, 2000;Svensson and Hein, 2004).…”

Section: Molecular Basis For Altered Function Of Nat2 Polymorphic Varmentioning

confidence: 76%

N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

2006

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A role for the N-acetyltransferase 2 (NAT2) genetic polymorphism in cancer risk has been the subject of numerous studies. Although comprehensive reviews of the NAT2 acetylation polymorphism have been published elsewhere, the objective of this paper is to briefly highlight some important features of the NAT2 acetylation polymorphism that are not universally accepted to better understand the role of NAT2 polymorphism in carcinogenic risk assessment. NAT2 slow acetylator phenotype(s) infer a consistent and robust increase in urinary bladder cancer risk following exposures to aromatic amine carcinogens. However, identification of specific carcinogens is important as the effect of NAT2 polymorphism on urinary bladder cancer differs dramatically between monoarylamines and diarylamines. Misclassifications of carcinogen exposure and NAT2 genotype/phenotype confound evidence for a real biological effect. Functional understanding of the effects of NAT2 genetic polymorphisms on metabolism and genotoxicity, tissue-specific expression and the elucidation of the molecular mechanisms responsible are critical for the interpretation of previous and future human molecular epidemiology investigations into the role of NAT2 polymorphism on cancer risk. Although associations have been reported for various cancers, this paper focuses on urinary bladder cancer, a cancer in which a role for NAT2 polymorphism was first proposed and for which evidence is accumulating that the effect is biologically significant with important public health implications.

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Section: Molecular Basis For Altered Function Of Nat2 Polymorphic Varmentioning

confidence: 76%

N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

2006

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“…Slow acetylators can be underestimated when only a few SNPs are used to predict the phenotype (10). The degree of misclassification in the prediction of the phenotype from the NAT2 genotype has been estimated to be up to 7% (13,(22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

Variation of theN-Acetyltransferase 2Gene in a Romanian and a Kyrgyz Population

Rabstein

Unfried²,

Ranft³

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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As part of a project on environmental disasters in minority populations, this study aimed to evaluate differences in the sequence of N-acetyltransferase 2 (NAT2) as a metabolic susceptibility gene in yet unexplored ethnicities. Eight single nucleotide polymorphisms (SNP) in the NAT2 coding region and a variant in the 3V flanking region were analyzed in 290 unrelated Kyrgyz and 140 unrelated Romanians by SNP-specific PCR analysis. The variants 341C, 481T, and 803G were less and 857A more prevalent in Kyrgyz (P < 0.0001). The variant at site 857 indicates Asian descent. 282C>T and 590G>A showed no significant variation by ethnicity. 364G>A and 411A>T turned out to be monomorphic. Database comparisons of the NAT2 minor allele frequencies support that Romanians belong to Caucasians and Kyrgyz are in between Caucasians and East Asians. The distributions of predicted haplotypes differed significantly between the two ethnicities where the Kyrgyz showed a higher genetic diversity. The haplotype without mutations was more common in Kyrgyz (40.1% in Kyrgyz, 29.3% in Romanians). Accordingly, the imputed slow acetylator phenotype was less prevalent in Kyrgyz (35.2% versus 51.4% in Romanians). We found pronounced ethnic differences in NAT2 genotypes with yet unknown effect on the health risks for environmental or occupational exposures in minority populations. (Cancer Epidemiol Biomarkers Prev 2006;15(1):138 -41)

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“…Interestingly, an earlier report had noted that the prevalence of apparent slow acetylation phenotype was greater in AIDS patients with acute illnesses (27 out of 29, 93%) compared with control subjects (18 out of 29, 62%) (Lee et al, 1993). A subsequent study compared 30 AIDS patients (with and without an acute illness) with 30 healthy control subjects for their NAT2 acetylation phenotype and genotype and reported numerous discrepancies between phenotype and genotype (O'Neil et al, 2000a).…”

Section: Downloaded Frommentioning

confidence: 99%

Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

Shah¹,

2014

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Phenoconversion transiently converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, potentially with corresponding changes in clinical response. This phenomenon, typically resulting from coadministration of medications that inhibit certain drug metabolizing enzymes (DMEs), is especially well documented for enzymes of the cytochrome P450 family. Nonclinical evidence gathered over the last two decades also strongly implicates elevated levels of some proinflammatory cytokines, released during inflammation, in down-regulation of drug metabolism, especially by certain DMEs of the P450 family, thereby potentially causing transient phenoconversion. Clinically, phenoconversion of NAT2, CYP2C19, and CYP2D6 has been documented in inflammatory conditions associated with elevated cytokines, such as human immunodeficiency virus infection, cancer, and liver disease. The potential of other inflammatory conditions to cause phenoconversion has not been studied but experimental and anecdotal clinical evidence supports infectioninduced down-regulation of CYP1A2, CYP3A4, and CYP2C9 as well. Collectively, the evidence supports a hypothesis that certain inflammatory conditions associated with elevated proinflammatory cytokines may cause phenoconversion of certain DMEs. Since inflammatory conditions associated with elevated levels of proinflammatory cytokines are highly prevalent, phenoconversion of genotypic EM patients into transient phenotypic PMs may be more frequent than appreciated. Since drug pharmacokinetics, and therefore the clinical response, is influenced by DME phenotype rather than genotype per se, phenoconversion (whatever its cause) can have a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies. There is a risk that focusing on genotype alone may miss important associations between clinical outcomes and DME phenotypes, thus compromising future prospects of personalized medicine.

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Acetylator phenotype and genotype in patients infected with HIV: discordance between methods for phenotype determination and genotype

Cited by 50 publications

References 26 publications

N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

Variation of theN-Acetyltransferase 2Gene in a Romanian and a Kyrgyz Population

Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

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