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Acetylator Phenotype

The Experts below are selected from a list of 168 Experts worldwide ranked by ideXlab platform

Adrian J Fretland – 1st expert on this subject based on the ideXlab platform

  • Acetylator Phenotype and Genotype in HIV‐Infected Patients with and without Sulfonamide Hypersensitivity
    The Journal of Clinical Pharmacology, 2020
    Co-Authors: William M. O'neil, David W Hein, Adrian J Fretland, Rodger David Macarthur, Marti J Farrough, Mark A Doll, Lawrence R. Crane, Craig K. Svensson

    Abstract:

    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.

  • Acetylator Phenotype and genotype in hiv infected patients with and without sulfonamide hypersensitivity
    The Journal of Clinical Pharmacology, 2002
    Co-Authors: William M Oneil, Adrian J Fretland, Rodger David Macarthur, Marti J Farrough, Mark A Doll

    Abstract:

    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.

  • Acetylator Phenotype and genotype in patients infected with hiv discordance between methods for Phenotype determination and genotype
    Pharmacogenetics, 2000
    Co-Authors: William M Oneil, David W Hein, Adrian J Fretland, Rodger David Macarthur, Marti J Farrough, Mark A Doll, Lawrence R. Crane, Robert K Drobitch, Craig K. Svensson

    Abstract:

    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.

Mark A Doll – 2nd expert on this subject based on the ideXlab platform

  • Acetylator Phenotype and Genotype in HIV‐Infected Patients with and without Sulfonamide Hypersensitivity
    The Journal of Clinical Pharmacology, 2020
    Co-Authors: William M. O'neil, David W Hein, Adrian J Fretland, Rodger David Macarthur, Marti J Farrough, Mark A Doll, Lawrence R. Crane, Craig K. Svensson

    Abstract:

    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.

  • 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, 2017
    Co-Authors: David W Hein, Mark A Doll

    Abstract:

    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.

  • the t341c ile114thr polymorphism of n acetyltransferase 2 yields slow Acetylator Phenotype by enhanced protein degradation
    Pharmacogenetics, 2004
    Co-Authors: Yu Zang, Mark A Doll, Shuang Zhao, Christopher J States, David W Hein

    Abstract:

    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.

David W Hein – 3rd expert on this subject based on the ideXlab platform

  • Acetylator Phenotype and Genotype in HIV‐Infected Patients with and without Sulfonamide Hypersensitivity
    The Journal of Clinical Pharmacology, 2020
    Co-Authors: William M. O'neil, David W Hein, Adrian J Fretland, Rodger David Macarthur, Marti J Farrough, Mark A Doll, Lawrence R. Crane, Craig K. Svensson

    Abstract:

    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.

  • 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, 2017
    Co-Authors: David W Hein, Mark A Doll

    Abstract:

    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.

  • the t341c ile114thr polymorphism of n acetyltransferase 2 yields slow Acetylator Phenotype by enhanced protein degradation
    Pharmacogenetics, 2004
    Co-Authors: Yu Zang, Mark A Doll, Shuang Zhao, Christopher J States, David W Hein

    Abstract:

    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.