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Adrian J Fretland - One of the best experts on this subject based on the ideXlab platform.
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Acetylator Phenotype and Genotype in HIV‐Infected Patients with and without Sulfonamide Hypersensitivity
The Journal of Clinical Pharmacology, 2020Co-Authors: William M. O'neil, David W Hein, Rodger David Macarthur, Marti J Farrough, Mark A Doll, Adrian J Fretland, Lawrence R. Crane, Craig K. SvenssonAbstract:Adverse reactions to sulfonamides occur at a higher frequency in patients infected with the human immunodeficiency virus (HIV) than noninfected patients. Some studies have suggested that patients with the slow Acetylator Phenotype are predisposed to these reactions, whereas other studies suggest that the slow Acetylator genotype is not a predisposing factor. To rationalize these seemingly contradictory observations, the authors determined the N-acetyltransferase 2 (NAT2) genotype and Phenotype in patients with and without a history of hypersensitivity reactions to sulfonamides. HIV-infected patients with a history of a delayed-type hypersensitivity reaction to trimethoprim-sulfamethoxazole were enrolled, along with a group of AIDS patients with no history of hypersensitivity (delayed or immediate). NAT2 Phenotype was determined in both groups using dapsone, while the genotype was determined using a polymerase chain reaction-restriction fragment length polymorphism assay. Ten of 14 patients (71%) with a history of hypersensitivity exhibited the slow Acetylator Phenotype, while 8 of 14 patients (57%) without such a history exhibited this same Phenotype (odds ratio [OR] = 1.9, 95% confidence interval [CI] = 0.4-9.0; p = 0.69, Fisher's Exact Test). While 9 of 14 patients (64%) with a history of hypersensitivity exhibited a slow Acetylator genotype, only 4 of 14 patients (29%) without such a history exhibited this genotype (ns). There were more instances of discordance between deduced and actual Phenotype in the nonhypersensitive patients (n = 4) than in the hypersensitive patients (n = 1). The reported higher frequency of the slow Acetylator Phenotype among patients with a history of hypersensitivity to sulfonamides does not appear to be explained by metabolic changes that would cause discordance between Acetylator genotype and Phenotype.
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Acetylator Phenotype and genotype in hiv infected patients with and without sulfonamide hypersensitivity
The Journal of Clinical Pharmacology, 2002Co-Authors: William M Oneil, Rodger David Macarthur, Marti J Farrough, Mark A Doll, Adrian J FretlandAbstract:Adverse reactions to sulfonamides occur at a higher frequency in patients infected with the human immunodeficiency virus (HIV) than noninfected patients. Some studies have suggested that patients with the slow Acetylator Phenotype are predisposed to these reactions, whereas other studies suggest that the slow Acetylator genotype is not a predisposing factor. To rationalize these seemingly contradictory observations, the authors determined the N-acetyltransferase 2 (NAT2) genotype and Phenotype in patients with and without a history of hypersensitivity reactions to sulfonamides. HIV-infected patients with a history of a delayed-type hypersensitivity reaction to trimethoprim-sulfamethoxazole were enrolled, along with a group of AIDS patients with no history of hypersensitivity (delayed or immediate). NAT2 Phenotype was determined in both groups using dapsone, while the genotype was determined using a polymerase chain reaction-restriction fragment length polymorphism assay. Ten of 14 patients (71%) with a history of hypersensitivity exhibited the slow Acetylator Phenotype, while 8 of 14 patients (57%) without such a history exhibited this same Phenotype (odds ratio [OR] = 1.9, 95% confidence interval [CI] = 0.4-9.0; p = 0.69, Fisher's Exact Test). While 9 of 14 patients (64%) with a history of hypersensitivity exhibited a slow Acetylator genotype, only 4 of 14 patients (29%) without such a history exhibited this genotype (ns). There were more instances of discordance between deduced and actual Phenotype in the nonhypersensitive patients (n = 4) than in the hypersensitive patients (n = 1). The reported higher frequency of the slow Acetylator Phenotype among patients with a history of hypersensitivity to sulfonamides does not appear to be explained by metabolic changes that would cause discordance between Acetylator genotype and Phenotype.
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Acetylator Phenotype and genotype in patients infected with hiv discordance between methods for Phenotype determination and genotype
Pharmacogenetics, 2000Co-Authors: William M Oneil, David W Hein, Rodger David Macarthur, Marti J Farrough, Mark A Doll, Adrian J Fretland, Lawrence R. Crane, Robert K Drobitch, Craig K. SvenssonAbstract:The Acetylator Phenotype and genotype of AIDS patients, with and without an acute illness, was compared with that of healthy control subjects (30 per group). Two probe drugs, caffeine and dapsone, were used to determine the Phenotype in the acutely ill cohort. Polymerase chain reaction amplification and restriction fragment length polymorphism analysis served to distinguish between the 26 known NAT2 alleles and the 21 most common NATI alleles. The distribution (%) of slow:rapid Acetylator Phenotype seen among acutely ill AIDS patients differed with the probe substrate used: 70:30 with caffeine versus 53:47 with dapsone. Phenotype assignment differed considerably between the two methods and there were numerous discrepancies between Phenotype and genotype. The NAT2 genotype distribution was 45:55 slow:rapid. Control subjects, Phenotyped only with caffeine, were 67:33 slow:rapid versus 60:40 genotypically. Stable AIDS patients, Phenotyped only with dapsone, were 55:45 slow:rapid versus 46:54 genotypically. Following resolution of their acute infections, 12 of the acutely ill subjects were rePhenotyped with dapsone. Phenotype assignment remained unchanged in all cases. The distribution of NATI alleles was similar in all three groups. It is evident from the amount of discordance between caffeine Phenotype and dapsone Phenotype or genotype that caution should be exercised in the use of caffeine as a probe for NAT2 in acutely ill patients. It is also clear that meaningful study of the acetylation polymorphism requires both phenotypic and genotypic data.
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novel human n acetyltransferase 2 alleles that differ in mechanism for slow Acetylator Phenotype
Journal of Biological Chemistry, 1999Co-Authors: Matthew A Leff, Adrian J Fretland, Mark A Doll, David W HeinAbstract:Abstract Three novel human NAT2 alleles (NAT2*5D, NAT2*6D, and NAT2*14G) were identified and characterized in a yeast expression system. The common rapid (NAT2*4) and slow (NAT2*5B) Acetylator human NAT2 alleles were also characterized for comparison. The novel recombinant NAT2 allozymes catalyzed bothN- and O-acetyltransferase activities at levels comparable with NAT2 5B and significantly below NAT2 4, suggesting that they confer slow acetylation Phenotype. In order to investigate the molecular mechanism of slow acetylation in the novel NAT2alleles, we assessed mRNA and protein expression levels and protein stability. No differences were observed in NAT2 mRNA expression among the novel alleles, NAT2*4 andNAT2*5B. However NAT2 5B and NAT2 5D, but not NAT2 6D and NAT2 14G protein expression were significantly lower than NAT2 4. In contrast, NAT2 6D was slightly (3.4-fold) and NAT2 14G was substantially (29-fold) less stable than NAT2 4. These results suggest that the 341T → C (Ile114 → Thr) common to the NAT2*5 cluster is sufficient for reduction in NAT2 protein expression, but that mechanisms for slow Acetylator Phenotype differ for NAT2 alleles that do not contain 341T → C, such as the NAT2*6 and NAT2*14 clusters. Different mechanisms for slow Acetylator Phenotype in humans are consistent with multiple slow Acetylator Phenotypes.
Mark A Doll - One of the best experts on this subject based on the ideXlab platform.
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Acetylator Phenotype and Genotype in HIV‐Infected Patients with and without Sulfonamide Hypersensitivity
The Journal of Clinical Pharmacology, 2020Co-Authors: William M. O'neil, David W Hein, Rodger David Macarthur, Marti J Farrough, Mark A Doll, Adrian J Fretland, Lawrence R. Crane, Craig K. SvenssonAbstract:Adverse reactions to sulfonamides occur at a higher frequency in patients infected with the human immunodeficiency virus (HIV) than noninfected patients. Some studies have suggested that patients with the slow Acetylator Phenotype are predisposed to these reactions, whereas other studies suggest that the slow Acetylator genotype is not a predisposing factor. To rationalize these seemingly contradictory observations, the authors determined the N-acetyltransferase 2 (NAT2) genotype and Phenotype in patients with and without a history of hypersensitivity reactions to sulfonamides. HIV-infected patients with a history of a delayed-type hypersensitivity reaction to trimethoprim-sulfamethoxazole were enrolled, along with a group of AIDS patients with no history of hypersensitivity (delayed or immediate). NAT2 Phenotype was determined in both groups using dapsone, while the genotype was determined using a polymerase chain reaction-restriction fragment length polymorphism assay. Ten of 14 patients (71%) with a history of hypersensitivity exhibited the slow Acetylator Phenotype, while 8 of 14 patients (57%) without such a history exhibited this same Phenotype (odds ratio [OR] = 1.9, 95% confidence interval [CI] = 0.4-9.0; p = 0.69, Fisher's Exact Test). While 9 of 14 patients (64%) with a history of hypersensitivity exhibited a slow Acetylator genotype, only 4 of 14 patients (29%) without such a history exhibited this genotype (ns). There were more instances of discordance between deduced and actual Phenotype in the nonhypersensitive patients (n = 4) than in the hypersensitive patients (n = 1). The reported higher frequency of the slow Acetylator Phenotype among patients with a history of hypersensitivity to sulfonamides does not appear to be explained by metabolic changes that would cause discordance between Acetylator genotype and Phenotype.
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catalytic properties and heat stabilities of novel recombinant human n acetyltransferase 2 allozymes support existence of genetic heterogeneity within the slow Acetylator Phenotype
Archives of Toxicology, 2017Co-Authors: David W Hein, Mark A DollAbstract:Human N-acetyltransferase 2 (NAT2) catalyzes the N-acetylation of numerous aromatic amine drugs such as sulfamethazine (SMZ) and hydrazine drugs such as isoniazid (INH). NAT2 also catalyzes the N-acetylation of aromatic amine carcinogens such as 2-aminofluorene and the O- and N,O-acetylation of aromatic amine and heterocyclic amine metabolites. Genetic polymorphism in NAT2 modifies drug efficacy and toxicity as well as cancer risk. Acetyltransferase catalytic activities and heat stability associated with six novel NAT2 haplotypes (NAT2*6C, NAT2*14C, NAT2*14D, NAT2*14E, NAT2*17, and NAT2*18) were compared with that of the reference NAT2*4 haplotype following recombinant expression in Escherichia coli. N-acetyltransferase activities towards SMZ and INH were significantly (p 0.05) from recombinant NAT2 4. The apparent Vmax catalyzed by NAT2 14C and NAT2 14D were significantly lower (p < 0.05) than the apparent Vmax catalyzed by NAT2 6C and NAT2 14E towards AF, ABP, and DMABP. Heat inactivation rate constants for recombinant human NAT2 14C, 14D, 14E, and 18 were significantly (p < 0.05) higher than NAT2 4. These results provide further evidence of genetic heterogeneity within the NAT2 slow Acetylator Phenotype.
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the t341c ile114thr polymorphism of n acetyltransferase 2 yields slow Acetylator Phenotype by enhanced protein degradation
Pharmacogenetics, 2004Co-Authors: Yu Zang, Mark A Doll, Shuang Zhao, Christopher J States, David W HeinAbstract:Objectives Human N-acetyltransferase 2 (NAT2) plays a significant role in the clearance and biotransformation of many drugs and carcinogens. A T 341 C (Ile114Thr) single nucleotide polymorphism (SNP) of NAT2 is commonly found in slow Acetylators, leading to altered drug response and toxicity and possibly cancer susceptibility from carcinogens. The objective of this study was to investigate the mechanism by which this SNP causes slow Acetylator Phenotype. Methods A cDNA expression system was used to compare the NAT2*4 reference allele with an identical one possessing the T 341 C SNP in COS-1 cells. The recombinant human NAT2 enzymes were compared in regard to catalytic activity, kinetic parameters, thermostability, immunoreactive protein level, mRNA level and in-vivo protein degradation. Results The T 341 C (Ile114Thr) SNP significantly reduced enzyme activity without changing the apparent kinetic parameters K m and V max (normalized for NAT2 protein), indicating that Ile114Thr did not change substrate or cofactor binding affinities or catalytic efficiency. Furthermore, no significant difference in NAT2 mRNA level was observed, indicating no impairment of transcription. The T 341 C (Ile114Thr) SNP did not alter thermostability of NAT2 at either 37 or 50°C. However, this SNP significantly reduced cytosolic NAT2 immunoreactive protein through enhanced protein degradation. Conclusion This is the first report indicating that protein degradation is an important mechanism of human NAT2 slow Acetylator Phenotype.
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Acetylator Phenotype and genotype in hiv infected patients with and without sulfonamide hypersensitivity
The Journal of Clinical Pharmacology, 2002Co-Authors: William M Oneil, Rodger David Macarthur, Marti J Farrough, Mark A Doll, Adrian J FretlandAbstract:Adverse reactions to sulfonamides occur at a higher frequency in patients infected with the human immunodeficiency virus (HIV) than noninfected patients. Some studies have suggested that patients with the slow Acetylator Phenotype are predisposed to these reactions, whereas other studies suggest that the slow Acetylator genotype is not a predisposing factor. To rationalize these seemingly contradictory observations, the authors determined the N-acetyltransferase 2 (NAT2) genotype and Phenotype in patients with and without a history of hypersensitivity reactions to sulfonamides. HIV-infected patients with a history of a delayed-type hypersensitivity reaction to trimethoprim-sulfamethoxazole were enrolled, along with a group of AIDS patients with no history of hypersensitivity (delayed or immediate). NAT2 Phenotype was determined in both groups using dapsone, while the genotype was determined using a polymerase chain reaction-restriction fragment length polymorphism assay. Ten of 14 patients (71%) with a history of hypersensitivity exhibited the slow Acetylator Phenotype, while 8 of 14 patients (57%) without such a history exhibited this same Phenotype (odds ratio [OR] = 1.9, 95% confidence interval [CI] = 0.4-9.0; p = 0.69, Fisher's Exact Test). While 9 of 14 patients (64%) with a history of hypersensitivity exhibited a slow Acetylator genotype, only 4 of 14 patients (29%) without such a history exhibited this genotype (ns). There were more instances of discordance between deduced and actual Phenotype in the nonhypersensitive patients (n = 4) than in the hypersensitive patients (n = 1). The reported higher frequency of the slow Acetylator Phenotype among patients with a history of hypersensitivity to sulfonamides does not appear to be explained by metabolic changes that would cause discordance between Acetylator genotype and Phenotype.
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Acetylator Phenotype and genotype in patients infected with hiv discordance between methods for Phenotype determination and genotype
Pharmacogenetics, 2000Co-Authors: William M Oneil, David W Hein, Rodger David Macarthur, Marti J Farrough, Mark A Doll, Adrian J Fretland, Lawrence R. Crane, Robert K Drobitch, Craig K. SvenssonAbstract:The Acetylator Phenotype and genotype of AIDS patients, with and without an acute illness, was compared with that of healthy control subjects (30 per group). Two probe drugs, caffeine and dapsone, were used to determine the Phenotype in the acutely ill cohort. Polymerase chain reaction amplification and restriction fragment length polymorphism analysis served to distinguish between the 26 known NAT2 alleles and the 21 most common NATI alleles. The distribution (%) of slow:rapid Acetylator Phenotype seen among acutely ill AIDS patients differed with the probe substrate used: 70:30 with caffeine versus 53:47 with dapsone. Phenotype assignment differed considerably between the two methods and there were numerous discrepancies between Phenotype and genotype. The NAT2 genotype distribution was 45:55 slow:rapid. Control subjects, Phenotyped only with caffeine, were 67:33 slow:rapid versus 60:40 genotypically. Stable AIDS patients, Phenotyped only with dapsone, were 55:45 slow:rapid versus 46:54 genotypically. Following resolution of their acute infections, 12 of the acutely ill subjects were rePhenotyped with dapsone. Phenotype assignment remained unchanged in all cases. The distribution of NATI alleles was similar in all three groups. It is evident from the amount of discordance between caffeine Phenotype and dapsone Phenotype or genotype that caution should be exercised in the use of caffeine as a probe for NAT2 in acutely ill patients. It is also clear that meaningful study of the acetylation polymorphism requires both phenotypic and genotypic data.
David W Hein - One of the best experts on this subject based on the ideXlab platform.
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Acetylator Phenotype and Genotype in HIV‐Infected Patients with and without Sulfonamide Hypersensitivity
The Journal of Clinical Pharmacology, 2020Co-Authors: William M. O'neil, David W Hein, Rodger David Macarthur, Marti J Farrough, Mark A Doll, Adrian J Fretland, Lawrence R. Crane, Craig K. SvenssonAbstract:Adverse reactions to sulfonamides occur at a higher frequency in patients infected with the human immunodeficiency virus (HIV) than noninfected patients. Some studies have suggested that patients with the slow Acetylator Phenotype are predisposed to these reactions, whereas other studies suggest that the slow Acetylator genotype is not a predisposing factor. To rationalize these seemingly contradictory observations, the authors determined the N-acetyltransferase 2 (NAT2) genotype and Phenotype in patients with and without a history of hypersensitivity reactions to sulfonamides. HIV-infected patients with a history of a delayed-type hypersensitivity reaction to trimethoprim-sulfamethoxazole were enrolled, along with a group of AIDS patients with no history of hypersensitivity (delayed or immediate). NAT2 Phenotype was determined in both groups using dapsone, while the genotype was determined using a polymerase chain reaction-restriction fragment length polymorphism assay. Ten of 14 patients (71%) with a history of hypersensitivity exhibited the slow Acetylator Phenotype, while 8 of 14 patients (57%) without such a history exhibited this same Phenotype (odds ratio [OR] = 1.9, 95% confidence interval [CI] = 0.4-9.0; p = 0.69, Fisher's Exact Test). While 9 of 14 patients (64%) with a history of hypersensitivity exhibited a slow Acetylator genotype, only 4 of 14 patients (29%) without such a history exhibited this genotype (ns). There were more instances of discordance between deduced and actual Phenotype in the nonhypersensitive patients (n = 4) than in the hypersensitive patients (n = 1). The reported higher frequency of the slow Acetylator Phenotype among patients with a history of hypersensitivity to sulfonamides does not appear to be explained by metabolic changes that would cause discordance between Acetylator genotype and Phenotype.
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catalytic properties and heat stabilities of novel recombinant human n acetyltransferase 2 allozymes support existence of genetic heterogeneity within the slow Acetylator Phenotype
Archives of Toxicology, 2017Co-Authors: David W Hein, Mark A DollAbstract:Human N-acetyltransferase 2 (NAT2) catalyzes the N-acetylation of numerous aromatic amine drugs such as sulfamethazine (SMZ) and hydrazine drugs such as isoniazid (INH). NAT2 also catalyzes the N-acetylation of aromatic amine carcinogens such as 2-aminofluorene and the O- and N,O-acetylation of aromatic amine and heterocyclic amine metabolites. Genetic polymorphism in NAT2 modifies drug efficacy and toxicity as well as cancer risk. Acetyltransferase catalytic activities and heat stability associated with six novel NAT2 haplotypes (NAT2*6C, NAT2*14C, NAT2*14D, NAT2*14E, NAT2*17, and NAT2*18) were compared with that of the reference NAT2*4 haplotype following recombinant expression in Escherichia coli. N-acetyltransferase activities towards SMZ and INH were significantly (p 0.05) from recombinant NAT2 4. The apparent Vmax catalyzed by NAT2 14C and NAT2 14D were significantly lower (p < 0.05) than the apparent Vmax catalyzed by NAT2 6C and NAT2 14E towards AF, ABP, and DMABP. Heat inactivation rate constants for recombinant human NAT2 14C, 14D, 14E, and 18 were significantly (p < 0.05) higher than NAT2 4. These results provide further evidence of genetic heterogeneity within the NAT2 slow Acetylator Phenotype.
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the t341c ile114thr polymorphism of n acetyltransferase 2 yields slow Acetylator Phenotype by enhanced protein degradation
Pharmacogenetics, 2004Co-Authors: Yu Zang, Mark A Doll, Shuang Zhao, Christopher J States, David W HeinAbstract:Objectives Human N-acetyltransferase 2 (NAT2) plays a significant role in the clearance and biotransformation of many drugs and carcinogens. A T 341 C (Ile114Thr) single nucleotide polymorphism (SNP) of NAT2 is commonly found in slow Acetylators, leading to altered drug response and toxicity and possibly cancer susceptibility from carcinogens. The objective of this study was to investigate the mechanism by which this SNP causes slow Acetylator Phenotype. Methods A cDNA expression system was used to compare the NAT2*4 reference allele with an identical one possessing the T 341 C SNP in COS-1 cells. The recombinant human NAT2 enzymes were compared in regard to catalytic activity, kinetic parameters, thermostability, immunoreactive protein level, mRNA level and in-vivo protein degradation. Results The T 341 C (Ile114Thr) SNP significantly reduced enzyme activity without changing the apparent kinetic parameters K m and V max (normalized for NAT2 protein), indicating that Ile114Thr did not change substrate or cofactor binding affinities or catalytic efficiency. Furthermore, no significant difference in NAT2 mRNA level was observed, indicating no impairment of transcription. The T 341 C (Ile114Thr) SNP did not alter thermostability of NAT2 at either 37 or 50°C. However, this SNP significantly reduced cytosolic NAT2 immunoreactive protein through enhanced protein degradation. Conclusion This is the first report indicating that protein degradation is an important mechanism of human NAT2 slow Acetylator Phenotype.
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Acetylator Phenotype and genotype in patients infected with hiv discordance between methods for Phenotype determination and genotype
Pharmacogenetics, 2000Co-Authors: William M Oneil, David W Hein, Rodger David Macarthur, Marti J Farrough, Mark A Doll, Adrian J Fretland, Lawrence R. Crane, Robert K Drobitch, Craig K. SvenssonAbstract:The Acetylator Phenotype and genotype of AIDS patients, with and without an acute illness, was compared with that of healthy control subjects (30 per group). Two probe drugs, caffeine and dapsone, were used to determine the Phenotype in the acutely ill cohort. Polymerase chain reaction amplification and restriction fragment length polymorphism analysis served to distinguish between the 26 known NAT2 alleles and the 21 most common NATI alleles. The distribution (%) of slow:rapid Acetylator Phenotype seen among acutely ill AIDS patients differed with the probe substrate used: 70:30 with caffeine versus 53:47 with dapsone. Phenotype assignment differed considerably between the two methods and there were numerous discrepancies between Phenotype and genotype. The NAT2 genotype distribution was 45:55 slow:rapid. Control subjects, Phenotyped only with caffeine, were 67:33 slow:rapid versus 60:40 genotypically. Stable AIDS patients, Phenotyped only with dapsone, were 55:45 slow:rapid versus 46:54 genotypically. Following resolution of their acute infections, 12 of the acutely ill subjects were rePhenotyped with dapsone. Phenotype assignment remained unchanged in all cases. The distribution of NATI alleles was similar in all three groups. It is evident from the amount of discordance between caffeine Phenotype and dapsone Phenotype or genotype that caution should be exercised in the use of caffeine as a probe for NAT2 in acutely ill patients. It is also clear that meaningful study of the acetylation polymorphism requires both phenotypic and genotypic data.
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novel human n acetyltransferase 2 alleles that differ in mechanism for slow Acetylator Phenotype
Journal of Biological Chemistry, 1999Co-Authors: Matthew A Leff, Adrian J Fretland, Mark A Doll, David W HeinAbstract:Abstract Three novel human NAT2 alleles (NAT2*5D, NAT2*6D, and NAT2*14G) were identified and characterized in a yeast expression system. The common rapid (NAT2*4) and slow (NAT2*5B) Acetylator human NAT2 alleles were also characterized for comparison. The novel recombinant NAT2 allozymes catalyzed bothN- and O-acetyltransferase activities at levels comparable with NAT2 5B and significantly below NAT2 4, suggesting that they confer slow acetylation Phenotype. In order to investigate the molecular mechanism of slow acetylation in the novel NAT2alleles, we assessed mRNA and protein expression levels and protein stability. No differences were observed in NAT2 mRNA expression among the novel alleles, NAT2*4 andNAT2*5B. However NAT2 5B and NAT2 5D, but not NAT2 6D and NAT2 14G protein expression were significantly lower than NAT2 4. In contrast, NAT2 6D was slightly (3.4-fold) and NAT2 14G was substantially (29-fold) less stable than NAT2 4. These results suggest that the 341T → C (Ile114 → Thr) common to the NAT2*5 cluster is sufficient for reduction in NAT2 protein expression, but that mechanisms for slow Acetylator Phenotype differ for NAT2 alleles that do not contain 341T → C, such as the NAT2*6 and NAT2*14 clusters. Different mechanisms for slow Acetylator Phenotype in humans are consistent with multiple slow Acetylator Phenotypes.
E Karlsson - One of the best experts on this subject based on the ideXlab platform.
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procainamide induced lupus erythematosus like syndrome in relation to Acetylator Phenotype and plasma levels of procainamide
Acta Medica Scandinavica, 2009Co-Authors: C Sonnhag, E KarlssonAbstract:ABSTRACT To investigate the relationship between Acetylator Phenotype and the development of procainamide (PA)-induced systemic lupus erythematosus (SLE-like syndrome, 28 patients with chronic ventricular arrhythmias treated with PA were followed for one year. The therapy was guided by plasma monitoring in all patients in order to obtain the proposed therapeutic plasma level of PA. Nine patients (30%), both slow and rapid Acetylators, developed the SLE-like syndrome within one year. PA plasma levels were similar in both slow and rapid Acetylators and there was no difference in total dose or duration of therapy before development of the syndrome. Thus, the Acetylator Phenotype is probably of no or minor predictive importance when PA therapy is guided by plasma monitoring. On the other hand, the antinuclear antibodies appeared significantly more rapidly in patients developing the syndrome and could possibly be used as an indicator of the risk. The results support the hypothesis that the primary amino group structure of PA may be of importance in the induction of the SLE-like syndrome.
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Procainamide‐Induced Lupus Erythematosus‐like Syndrome in Relation to Acetylator Phenotype and Plasma Levels of Procainamide
Acta Medica Scandinavica, 2009Co-Authors: C Sonnhag, E KarlssonAbstract:ABSTRACT To investigate the relationship between Acetylator Phenotype and the development of procainamide (PA)-induced systemic lupus erythematosus (SLE-like syndrome, 28 patients with chronic ventricular arrhythmias treated with PA were followed for one year. The therapy was guided by plasma monitoring in all patients in order to obtain the proposed therapeutic plasma level of PA. Nine patients (30%), both slow and rapid Acetylators, developed the SLE-like syndrome within one year. PA plasma levels were similar in both slow and rapid Acetylators and there was no difference in total dose or duration of therapy before development of the syndrome. Thus, the Acetylator Phenotype is probably of no or minor predictive importance when PA therapy is guided by plasma monitoring. On the other hand, the antinuclear antibodies appeared significantly more rapidly in patients developing the syndrome and could possibly be used as an indicator of the risk. The results support the hypothesis that the primary amino group structure of PA may be of importance in the induction of the SLE-like syndrome.
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spontaneous systemic lupus erythematosus and Acetylator Phenotype
Acta Medica Scandinavica, 2009Co-Authors: Rutger Larsson, E Karlsson, Lilian MolinAbstract:Fifteen patients with spontaneous systemic lupus erythematosus (SLE) have been Phenotyped by determination of plasma isoniazid (INH) half-life. Seven patients had signs of renal insufficiency. Of the 15 patients, 13 were slow and only 2 rapid Acetylators. No correlation was found between the plasma INH half-lives and the renal function. Thus, there is the same marked predominance of slow Acetylators in patients with spontaneous SLE as in patients with the drug-induced SLE-like syndrome.
William M Oneil - One of the best experts on this subject based on the ideXlab platform.
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Acetylator Phenotype and genotype in hiv infected patients with and without sulfonamide hypersensitivity
The Journal of Clinical Pharmacology, 2002Co-Authors: William M Oneil, Rodger David Macarthur, Marti J Farrough, Mark A Doll, Adrian J FretlandAbstract:Adverse reactions to sulfonamides occur at a higher frequency in patients infected with the human immunodeficiency virus (HIV) than noninfected patients. Some studies have suggested that patients with the slow Acetylator Phenotype are predisposed to these reactions, whereas other studies suggest that the slow Acetylator genotype is not a predisposing factor. To rationalize these seemingly contradictory observations, the authors determined the N-acetyltransferase 2 (NAT2) genotype and Phenotype in patients with and without a history of hypersensitivity reactions to sulfonamides. HIV-infected patients with a history of a delayed-type hypersensitivity reaction to trimethoprim-sulfamethoxazole were enrolled, along with a group of AIDS patients with no history of hypersensitivity (delayed or immediate). NAT2 Phenotype was determined in both groups using dapsone, while the genotype was determined using a polymerase chain reaction-restriction fragment length polymorphism assay. Ten of 14 patients (71%) with a history of hypersensitivity exhibited the slow Acetylator Phenotype, while 8 of 14 patients (57%) without such a history exhibited this same Phenotype (odds ratio [OR] = 1.9, 95% confidence interval [CI] = 0.4-9.0; p = 0.69, Fisher's Exact Test). While 9 of 14 patients (64%) with a history of hypersensitivity exhibited a slow Acetylator genotype, only 4 of 14 patients (29%) without such a history exhibited this genotype (ns). There were more instances of discordance between deduced and actual Phenotype in the nonhypersensitive patients (n = 4) than in the hypersensitive patients (n = 1). The reported higher frequency of the slow Acetylator Phenotype among patients with a history of hypersensitivity to sulfonamides does not appear to be explained by metabolic changes that would cause discordance between Acetylator genotype and Phenotype.
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Acetylator Phenotype and genotype in patients infected with hiv discordance between methods for Phenotype determination and genotype
Pharmacogenetics, 2000Co-Authors: William M Oneil, David W Hein, Rodger David Macarthur, Marti J Farrough, Mark A Doll, Adrian J Fretland, Lawrence R. Crane, Robert K Drobitch, Craig K. SvenssonAbstract:The Acetylator Phenotype and genotype of AIDS patients, with and without an acute illness, was compared with that of healthy control subjects (30 per group). Two probe drugs, caffeine and dapsone, were used to determine the Phenotype in the acutely ill cohort. Polymerase chain reaction amplification and restriction fragment length polymorphism analysis served to distinguish between the 26 known NAT2 alleles and the 21 most common NATI alleles. The distribution (%) of slow:rapid Acetylator Phenotype seen among acutely ill AIDS patients differed with the probe substrate used: 70:30 with caffeine versus 53:47 with dapsone. Phenotype assignment differed considerably between the two methods and there were numerous discrepancies between Phenotype and genotype. The NAT2 genotype distribution was 45:55 slow:rapid. Control subjects, Phenotyped only with caffeine, were 67:33 slow:rapid versus 60:40 genotypically. Stable AIDS patients, Phenotyped only with dapsone, were 55:45 slow:rapid versus 46:54 genotypically. Following resolution of their acute infections, 12 of the acutely ill subjects were rePhenotyped with dapsone. Phenotype assignment remained unchanged in all cases. The distribution of NATI alleles was similar in all three groups. It is evident from the amount of discordance between caffeine Phenotype and dapsone Phenotype or genotype that caution should be exercised in the use of caffeine as a probe for NAT2 in acutely ill patients. It is also clear that meaningful study of the acetylation polymorphism requires both phenotypic and genotypic data.
