Role of N-Acetyltransferase Phenotypes in Bladder Carcinogenesis: A Pharmacogenetic Epidemiological Approach to Bladder Cancer

Cartwright, R.A.; Rogers, HowardJ.; Barham-Hall, D; Glashan, R. W.; Ahmad, RaadA.; Higgins, Elizabeth; Kahn, MohidA.

doi:10.1016/s0140-6736(82)90810-8

Cited by 437 publications

(161 citation statements)

References 13 publications

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“…Redox reactions are broadly linked to processes both normal and pathologic, but have particular relevance to cancer with glutathione metabolism playing both protective and pathologic roles. Loss of the glutathione S-transferase M1 gene (GSTM1) correlates with increased susceptibility to lung and bladder cancer (14,15), while elevated GSH in several tumors may confer resistance to chemo-and radiotherapy (16)(17)(18). These effects are thought to be secondary to cellular resistance to reactive oxygen species (ROS) including hydrogen peroxide and superoxide (19).…”

Section: Mri | Molecular Imaging | Probe | Kineticsmentioning

confidence: 99%

Hyperpolarized ¹³ C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging

Keshari

Kurhanewicz

Bok

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

151

159

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Reduction and oxidation (redox) chemistry is involved in both normal and abnormal cellular function, in processes as diverse as circadian rhythms and neurotransmission. Intracellular redox is maintained by coupled reactions involving NADPH, glutathione (GSH), and vitamin C, as well as their corresponding oxidized counterparts. In addition to functioning as enzyme cofactors, these reducing agents have a critical role in dealing with reactive oxygen species (ROS), the toxic products of oxidative metabolism seen as culprits in aging, neurodegenerative disease, and ischemia/ reperfusion injury. Despite this strong relationship between redox and human disease, methods to interrogate a redox pair in vivo are limited. Here we report the development of [1-13 C] dehydroascorbate [DHA], the oxidized form of Vitamin C, as an endogenous redox sensor for in vivo imaging using hyperpolarized 13 C spectroscopy. In murine models, hyperpolarized [1-13 C] DHA was rapidly converted to [1-13 C] vitamin C within the liver, kidneys, and brain, as well as within tumor in a transgenic prostate cancer mouse. This result is consistent with what has been previously described for the DHA/Vitamin C redox pair, and points to a role for hyperpolarized [1-13 C] DHA in characterizing the concentrations of key intracellular reducing agents, including GSH. More broadly, these findings suggest a prognostic role for this new redox sensor in determining vulnerability of both normal and abnormal tissues to ROS.MRI | molecular imaging | probe | kinetics

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Section: Mri | Molecular Imaging | Probe | Kineticsmentioning

confidence: 99%

Hyperpolarized ¹³ C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging

Keshari

Kurhanewicz

Bok

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

151

159

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“…The T341C SNP associated with NAT2 * 5 alleles yielded very large reductions in NAT2 protein and activity (Table 3). One of the original studies by Cartwright et al [29] is of particular interest for several reasons. First, the population studied had documented exposures to aromatic amine dyes.…”

Section: Human Epidemiological Investigationsmentioning

confidence: 99%

Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis

Hein

2002

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

458

387

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Aromatic and heterocyclic amines require metabolic activation to electrophilic intermediates that initiate carcinogenesis. N-Acetyltransferase 1 (NAT1) and 2 (NAT2) are important enzymes in the biotransformation of these carcinogens and exhibit genetic polymorphism. Human NAT1 and NAT2 alleles are listed at: http://www.louisville.edu/medschool/pharmacology/NAT. html by an international gene nomenclature committee. The high frequency of the NAT1 and NAT2 acetylation polymorphisms in human populations together with ubiquitous exposure to aromatic and heterocyclic amines suggest that NAT1 and NAT2 acetylator genotypes are important modifiers of human cancer susceptibility. For cancers in which N-acetylation is a detoxification step such as aromatic amine-related urinary bladder cancer, NAT2 slow acetylator phenotype is at higher risk. Multiple studies have shown that the urinary bladder cancer risk is particularly high in the slowest NAT2 acetylator phenotype or genotype (NAT2 * 5). In contrast, for cancers in which N-acetylation is negligible and O-acetylation is an activation step such as for heterocyclic amine-related colon cancer, NAT2 rapid acetylator phenotype is at higher risk. Although studies have found associations between NAT1 genotype and various cancers, the findings are less consistent and are not well understood. Since cancer risk requires exposure to aromatic and/or heterocyclic amine carcinogens modified by NAT1 and/or NAT2 acetylator genotype, the results from human epidemiology studies are dependent upon the quality and accuracy of the exposure assessment and genotype determination. Conclusions require understanding the relationship between genotype and phenotype, as well as the role of genetic variation in carcinogen metabolism, DNA repair, and host susceptibility. Investigations have been carried out in rapid and slow acetylator rodent models in which both exposure and genetic variability are tightly controlled. Human NAT1 and NAT2 alleles have been characterized by recombinant expression to further understand the effects of nucleotide polymorphisms on function and phenotype.

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“…7 Epidemiologic studies have shown that slow acetylator phenotype is associated with an increased risk of urothelial cancer, especially among occupationally exposed dye workers. 8,9 Genetic polymorphisms of NAT1 and NAT2 have been reported in Asians as well as Caucasians, and are well correlated with NAT activities. 10,11 In our previous study, those who are homozygous for low NAT2 activity alleles are predisposed for urothelial cancer in a Japanese population.…”

mentioning

confidence: 99%

Association of genotypes of carcinogen‐activating enzymes, phenol sulfotransferase SULT1A1 (ST1A3) and arylamine N‐acetyltransferase NAT2, with urothelial cancer in a Japanese population

Ozawa

Katoh

Inatomi

et al. 2002

Intl Journal of Cancer

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Carcinogenic aromatic amines such as 4-aminobiphenyl, which is contained in tobacco smoke, are one of the causal factors of urothelial epithelial cancers. 4-Aminobiphenyl has been shown to be bioactivated through N-hydroxylation by hepatic cytochrome (CYP) 1A2 and subsequently through O-sulfation and O-acetylation by phenol sulfating sulfotransferase, ST1A3 (SULT1A1), and arylamine N-acetyltransferase, NAT2, respectively. In a case-control study for urothelial epithelial cancers, low activity alleles of NAT2 are overall high-risk alleles (OR 2.11; 95% CI 1. Urothelial transitional cell carcinoma (bladder, ureter and renal pelvis) is one of the most serious health problems occurring in Japan. 1 Carcinogenic aromatic amines, such as 4-aminobiphenyl detected in cigarette smoke, are hypothesized to be a major causal factor for the etiology of urothelial cancers. 2 Carcinogenic aromatic amines are known to undergo N-hydroxylation by hepatic cytochrome P450s (CYPs). 3,4 Subsequently, the produced N-hydroxy aromatic amines are further O-acetylated and O-sulfated by arylamine N-acetyltransferase (NAT) and phenol (aryl) sulfotransferase (SULT), respectively, to yield highly reactive intermediates capable of binding to DNA. 3,5 NAT is composed of NAT1 and NAT2; the former is expressed in many human tissues including the uroepithelium and the latter is mainly expressed in the liver. 6 Both NAT1 and NAT2 have been shown to catalyze the O-acetylation of a number of carcinogenic N-hydroxy aromatic amines. 7 Epidemiologic studies have shown that slow acetylator phenotype is associated with an increased risk of urothelial cancer, especially among occupationally exposed dye workers. 8,9 Genetic polymorphisms of NAT1 and NAT2 have been reported in Asians as well as Caucasians, and are well correlated with NAT activities. 10,11 In our previous study, those who are homozygous for low NAT2 activity alleles are predisposed for urothelial cancer in a Japanese population. 12 Furthermore, individuals with combined NAT1*10 and NAT2 low activity allele(s) showed increased risk for urothelial cancer. 12 A form of phenol SULT, ST1A3 (SULT1A1), has been shown to efficiently catalyze the metabolic activation of an N-hydroxy derivative of 4-aminobiphenyl. 13,14 Different alleles of ST1A3 (SULT1A1) were reported as *2 (213Arg3His), *3 (223Met3Val) and *4 (37Arg3Gln). 15,16 We investigated allele frequency of the variant ST1A3 alleles in a Japanese population and calculated allele frequency of *1 and *2 as 0.83 and 0.17, respectively. Frequency of *3 was a rare allele (frequency less than 0.01). 17 ST1A3*2 has been shown to be unstable and to lose its enzymatic activity substantially faster than the wild-type ST1A3*1 did. 17,18 Role of the genetic polymorphism in ST1A3 (SULT1A1) in urothelial cancer susceptibility has never been evaluated, although the frequency of the *2 allele was relatively high in a Japanese population as well as Caucasians. 15,16 In our study, we evaluated effects of the different and relatively frequent allele of ST1A3 (SU...

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Role of N-Acetyltransferase Phenotypes in Bladder Carcinogenesis: A Pharmacogenetic Epidemiological Approach to Bladder Cancer

Cited by 437 publications

References 13 publications

Hyperpolarized ¹³ C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging

Hyperpolarized ¹³ C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging

Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis

Association of genotypes of carcinogen‐activating enzymes, phenol sulfotransferase SULT1A1 (ST1A3) and arylamine N‐acetyltransferase NAT2, with urothelial cancer in a Japanese population

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Role of N-Acetyltransferase Phenotypes in Bladder Carcinogenesis: A Pharmacogenetic Epidemiological Approach to Bladder Cancer

Cited by 437 publications

References 13 publications

Hyperpolarized 13 C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging

Hyperpolarized 13 C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging

Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis

Association of genotypes of carcinogen‐activating enzymes, phenol sulfotransferase SULT1A1 (ST1A3) and arylamine N‐acetyltransferase NAT2, with urothelial cancer in a Japanese population

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Hyperpolarized ¹³ C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging

Hyperpolarized ¹³ C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging