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Human N-acetyltransferase 1 10 and 11 alleles increase protein expression through distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity.

ABSTRACT: N-acetyltransferase 1 (NAT1) metabolizes drugs and environmental carcinogens. NAT1 alleles *10 and *11 have been proposed to alter protein level or enzyme activity compared with wild-type NAT1 *4 and to confer cancer risk, through uncertain pathways. This study characterizes regulatory polymorphisms and underlying mechanisms of NAT1 expression.We measured allelic NAT1 mRNA expression and translation, as a function of multiple transcription start sites, alternative splicing, and three 3'-polyadenylation sites in human livers (one of which was discovered in this study), B lymphocytes, and transfected cells. In a clinical study of 469 patients with HIV/AIDS treated with the NAT1/NAT2 substrate sulfamethoxazole (SMX), associations were tested between SMX-induced hypersensitivity and NAT1 *10 and *11 genotypes, together with known NAT2 polymorphisms.NAT1 *10 and *11 were determined to act as common regulatory alleles accounting for most NAT1 expression variability, both leading to increased translation into active protein. NAT1 *11 (2.4% minor allele frequency) affected 3'-polyadenylation site usage, thereby increasing formation of NAT1 mRNA with intermediate length 3'-untranslated region (major isoform) at the expense of the short isoform, resulting in more efficient protein translation. NAT1 *10 (19% minor allele frequency) increased translation efficiency without affecting 3'-untranslated region polyadenylation site usage. Livers and B-lymphocytes with *11/*4 and *10/*10 genotypes displayed higher NAT1 immunoreactivity and NAT1 enzyme activity than the reference genotype *4/*4. Patients who carry *10/*10 and *11/*4 (fast NAT1 acetylators) were less likely to develop hypersensitivity to SMX, but this was observed only in individuals who are also carrying a slow NAT2 acetylator genotype.NAT1 *10 and *11 significantly increase NAT1 protein level/enzyme activity, enabling the classification of carriers into reference and rapid acetylators. Rapid NAT1 acetylator status seems to protect against SMX toxicity by compensating for slow NAT2 acetylator status.

SUBMITTER: Wang D

PROVIDER: S-EPMC3172334 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Human N-acetyltransferase 1 10 and 11 alleles increase protein expression through distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity.

Wang Danxin D Para Michael F MF Koletar Susan L SL Sadee Wolfgang W

Pharmacogenetics and genomics 20111001 10

<h4>Objectives</h4>N-acetyltransferase 1 (NAT1) metabolizes drugs and environmental carcinogens. NAT1 alleles *10 and *11 have been proposed to alter protein level or enzyme activity compared with wild-type NAT1 *4 and to confer cancer risk, through uncertain pathways. This study characterizes regulatory polymorphisms and underlying mechanisms of NAT1 expression.<h4>Methods</h4>We measured allelic NAT1 mRNA expression and translation, as a function of multiple transcription start sites, alternat ...[more]

PMID: 21878835

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Project description:Antigen-presenting cells (APC) are thought to play an important role in the pathogenesis of drug-induced immune reactions. Various pathological factors can activate APC and therefore influence the immune equilibrium. It is interesting that several diseases have been associated with an increased rate of drug allergy. The aim of this project was to evaluate the impact of such "danger signals" on sulfamethoxazole (SMX) metabolism in human APC (peripheral blood mononuclear cells, Epstein-Barr virus-modified B lymphocytes, monocyte-derived dendritic cells, and two cell lines). APC were incubated with SMX (100 microM-2 mM; 5 min-24 h), in the presence of pathological factors: bacterial endotoxins (lipopolysaccharide and staphylococcal enterotoxin B), flu viral proteins, cytokines [interleukin (IL)-1beta, IL-6, IL-10; tumor necrosis factor-alpha; interferon-gamma; and transforming growth factor-beta], inflammatory molecules (prostaglandin E2, human serum complement, and activated protein C), oxidants (buthionine sulfoximine and H(2)O(2)), and hyperthermia (37.5-39.5 degrees C). Adduct formation was evaluated by enzyme-linked immunosorbent assay and confocal microscopy. SMX-protein adduct formation was time- and concentration-dependent for each cell type tested, in both physiological and danger conditions. A danger environment significantly increased the formation of SMX-protein adducts and significantly shortened the delay for their detection. An additive effect was observed with a combination of danger signals. Dimedone (chemical selectively binding cysteine sulfenic acid) and antioxidants decreased both baseline and danger-enhanced SMX-adduct formation. Various enzyme inhibitors were associated with a significant decrease in SMX-adduct levels, with a pattern varying depending on the cell type and the culture conditions. These results illustrate that danger signals enhance the formation of intracellular SMX-protein adducts in human APC. These findings might be relevant to the increased frequency of drug allergy in certain disease states.

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Human N-acetyltransferase 1 10 and 11 alleles increase protein expression through distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity.

Publications

Human N-acetyltransferase 1 10 and 11 alleles increase protein expression through distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity.

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Human N-acetyltransferase 1 *10 and *11 alleles increase protein expression through distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity.

Publications

Human N-acetyltransferase 1 *10 and *11 alleles increase protein expression through distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Human N-acetyltransferase 1 10 and 11 alleles increase protein expression through distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity.

Human N-acetyltransferase 1 10 and 11 alleles increase protein expression through distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity.