N-acetyltransferase

Evans, David A.

doi:10.1016/0163-7258(89)90036-3

Cited by 240 publications

(20 citation statements)

References 256 publications

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“…Detections were separately duplicated for quality control of genotyping. In brief, the three mutations 481C to T, 590 G to A and 857 G to A were detected by a PCR-RFLP (restriction fragment length polymorphism) method as described previously [17]. After PCR amplification using specific primers, the PCR products were digested with the restriction enzymes Kpn I, Taq I, and Bam HI to determine the nucleotide substitution at 481, 590, and 857, respectively.…”

Section: Methodsmentioning

confidence: 99%

NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: A randomized controlled trial for pharmacogenetics-based therapy

Azuma

Ohno

Kubota

et al. 2012

Eur J Clin Pharmacol

211

178

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ObjectiveThis study is a pharmacogenetic clinical trial designed to clarify whether the N-acetyltransferase 2 gene (NAT2) genotype-guided dosing of isoniazid improves the tolerability and efficacy of the 6-month four-drug standard regimen for newly diagnosed pulmonary tuberculosis.MethodsIn a multicenter, parallel, randomized, and controlled trial with a PROBE design, patients were assigned to either conventional standard treatment (STD-treatment: approx. 5 mg/kg of isoniazid for all) or NAT2 genotype-guided treatment (PGx-treatment: approx. 7.5 mg/kg for patients homozygous for NAT2*4: rapid acetylators; 5 mg/kg, patients heterozygous for NAT2*4: intermediate acetylators; 2.5 mg/kg, patients without NAT2*4: slow acetylators). The primary outcome included incidences of 1) isoniazid-related liver injury (INH-DILI) during the first 8 weeks of therapy, and 2) early treatment failure as indicated by a persistent positive culture or no improvement in chest radiographs at the8th week.ResultsOne hundred and seventy-two Japanese patients (slow acetylators, 9.3 %; rapid acetylators, 53.5 %) were enrolled in this trial. In the intention-to-treat (ITT) analysis, INH-DILI occurred in 78 % of the slow acetylators in the STD-treatment, while none of the slow acetylators in the PGx-treatment experienced either INH-DILI or early treatment failure. Among the rapid acetylators, early treatment failure was observed with a significantly lower incidence rate in the PGx-treatment than in the STD-treatment (15.0 % vs. 38 %). Thus, the NAT2 genotype-guided regimen resulted in much lower incidences of unfavorable events, INH-DILI or early treatment failure, than the conventional standard regimen.ConclusionOur results clearly indicate a great potential of the NAT2 genotype-guided dosing stratification of isoniazid in chemotherapy for tuberculosis.

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Section: Methodsmentioning

confidence: 99%

NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: A randomized controlled trial for pharmacogenetics-based therapy

Azuma

Ohno

Kubota

et al. 2012

Eur J Clin Pharmacol

211

178

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“…These include activation of a lupus diathesis (Alarcon-Segovia et al 1967) or a latent viral infection (Lerner et al 1974); immune response to drug (metabolite) or to drugaltered nucleoprotein-conjugate (Allison 1971;Cornacchia et al 1988;Rubin 1988;Weigle 1973;Wheeler et al 1991;Yamauchi et al 1975); loss of tolerance following drug-protein conjugation (hapten-carrier complex) via bioactivation Park & Kitteringham 1990;Roberts et al 1989;Uetrecht et al 1984;Wheeler et al 1991); drugs acting as polyclonal activators or adjuvants in vivo Ochi et al 1983;Rubin 1988;Yu & Ziff 1985); effects on macrophage antigen recognition and processing; pharmacokinetic -a direct role of acetylation phenotype (Foad et al 1977;Freemen et al 1979;Price-Evans 1989;Price-Evans et al 1960;Reidenberg et al 1975;Weber & Hein 1985); and immunogenetic -a unique class II antigen encoded by the major histocompatibility complex which would control response to complement or account for the restricted antibody responses seen in DRL (Batchelor et al 1980;Fielder et al 1983;Fronek et al 1991;Hess 1988;Mitchell et al 1987Mitchell et al , 1990Schur et al 1990;Sim & Gill 1984;Totoritis et al 1988;Welch et al 1988). Frequently, studies of this nature in humans have attempted to focus on the expression of autoimmunity as an end result of exposure to punitive environmental chemicals or drugs without an appreciation or knowledge of other predisposing factors · such as age, sex, preexistent pathology, abnormal renal or liver metabolism and genetic polymorphism of the patient population.…”

Section: Mechanism(s) Of Induction Of Drlmentioning

confidence: 99%

Drug-Related Lupus

Adams

Hess

1991

Drug Safety

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Adverse side effects to drugs and chemicals in which immune mechanisms may be responsible have been described in drug-related lupus (DRL). The spectrum of drugs that may elicit DRL includes such classes as the hydrazines, arylamines, and chemicals that can be metabolised to amines. The 2 major pathways of metabolism--acetylation and N-hydroxylation--are described in detail. The events leading to autoantibody production are not well understood; however, specific consideration of the genetic makeup of patients who are candidates for treatment with these drugs may help identify those at risk of developing DRL.

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“…Proteins that catalyze the transacetylation of acetyl coenzyme A (Acetyl-CoA) to arylamines and arylalkylamines are commonly referred to as arylamine N -acetyltransferases and arylalkylamine N -acetyltransferases (aaNAT), respectively (Evans, 1989). In mammals, aaNAT is primarily involved in the synthesis of N -acetylserotonin.…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of two arylalkylamine N-acetyltransferases in the yellow fever mosquito, Aedes aegypti

Mehere

Han

Christensen

et al. 2011

Insect Biochemistry and Molecular Biology

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In this study we provide a molecular and biochemical identification of two arylalkylamine N-acetyltransferases (aaNAT) from Aedes aegypti mosquitoes. N-acetyldopamine, the enzyme product of aaNAT, was detected in Ae. aegypti, indicating the presence of an aaNAT in this mosquito. A BLAST search of the Ae. aegypti genome, using sequence information from an activity-verified Drosophila aaNAT, identified thirteen putative aaNAT sequences sharing 13-48% sequence identity with the Drosophila enzyme. Eight of the thirteen putative aaNAT proteins were expressed using a bacterial expression system. Screening of purified recombinant proteins against 5-hydroxytryptamine, dopamine, methoxytryptamine, norepinephrine, octopamine, tryptamine, and tyramine substrates, established that two of the putative aaNATs are active to the tested arylalkylamines. We therefore named them aaNAT1 and 2, respectively. Analysis of the transcriptional profiles of the two aaNAT genes from Ae. aegypti revealed that aaNAT1 is more abundant in the whole body of larvae and pupae, and aaNAT2 is more abundant in the head of adult mosquitoes. Based on their substrate and transcriptional profiles, together with previous reports from other insects, we suggest that the two aaNATs play diverse roles in Ae. aegypti, with aaNAT1 primarily involved in sclerotization and aaNAT2 mainly in neurotransmitter inactivation. Our data provide a beginning to a more comprehensive understanding of the biochemistry and physiology of aaNATs from the Ae. aegypti and serve as a reference for studying the aaNAT family of proteins from other insect species.

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N-acetyltransferase

Cited by 240 publications

References 256 publications

NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: A randomized controlled trial for pharmacogenetics-based therapy

NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: A randomized controlled trial for pharmacogenetics-based therapy

Drug-Related Lupus

Identification and characterization of two arylalkylamine N-acetyltransferases in the yellow fever mosquito, Aedes aegypti

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