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204. Polymorphisms of cytochrome P4501A2 and N -acetyltransferase genes, smoking, and risk of pancreatic cancer

Author

Li, Donghui, primary, Jiao, Li, additional, Li, Yanan, additional, Doll, Mark A., additional, Hein, David W., additional, Bondy, Melissa L., additional, Evans, Douglas B., additional, Wolff, Robert A., additional, Lenzi, Renato, additional, Pisters, Peter W., additional, Abbruzzese, James L., additional, and Hassan, Manal M., additional

Published
2005
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210. Association of metabolic gene polymorphisms with tobacco consumption in healthy controls

Author

Smits, Kim M., primary, Benhamou, Simone, additional, Garte, Seymour, additional, Weijenberg, Matty P., additional, Alamanos, Yannis, additional, Ambrosone, Christine, additional, Autrup, Herman, additional, Autrup, Judith L., additional, Baranova, Helena, additional, Bathum, Lisa, additional, Boffetta, Paolo, additional, Bouchardy, C., additional, Brockmoller, Jurgen, additional, Butkiewicz, Dorota, additional, Cascorbi, Ingolf, additional, Clapper, Margie L., additional, Coutelle, Christiane, additional, Daly, Ann K., additional, Muzi, Giacomo, additional, Dolzan, Vita, additional, Duzhak, Tatyana G., additional, Farker, Katrin, additional, Golka, Klaus, additional, Haugen, Aage, additional, Hein, David W., additional, Hildesheim, Allan, additional, Hirvonen, Ari, additional, Hsieh, Ling L., additional, Ingelman-Sundberg, Magnus, additional, Kalina, Ivan, additional, Kang, Daehee, additional, Katoh, Takahiko, additional, Kihara, Masahiro, additional, Ono-Kihara, Masako, additional, Kim, Heon, additional, Kiyohara, Chikako, additional, Kremers, Pierre, additional, Lazarus, Philip, additional, Le Marchand, Loic, additional, Lechner, Maria C., additional, London, Stephanie, additional, Manni, Johannes J., additional, Maugard, Christine M., additional, Morgan, Gareth J., additional, Morita, Shunji, additional, Nazar-Stewart, Valle, additional, Kristensen, Vessela Nedelcheva, additional, Oda, Yoshio, additional, Parl, Fritz F., additional, Peters, Wilbert H.M., additional, Rannug, Agneta, additional, Rebbeck, Timothy, additional, Pinto, Luis F. Ribeiro, additional, Risch, Angela, additional, Romkes, Marjorie, additional, ?alagovic, Jan, additional, Schoket, Bernadette, additional, Seidegard, Janeric, additional, Shields, Peter G., additional, Sim, Edith, additional, Sinnett, Daniel, additional, Strange, Richard C., additional, Stucker, Isabelle, additional, Sugimura, Haruhiko, additional, To-Figueras, Jordi, additional, Vineis, Paolo, additional, Yu, Mimi C., additional, Zheng, Wei, additional, Pedotti, Paola, additional, and Taioli, Emanuela, additional

Published
2004
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211. Pharmacogenomics: Social, Ethical, and Clinical Dimensions

Author

Hein, David W.

Abstract

Edited by Mark A. Rothstein. Hoboken, NJ: John Wiley & Sons, 2003. 320 pp. ISBN: 0 471-22769-2, $59.95 cloth. This interesting and timely book presents a multidisciplinary analysis of the [...]

Published
2003

224. Phenotypic and Genotypic Characterization of N-Acetylation.

Author

Kang, Y. James, Las, Lawrence H., Svensson, Craig K., and Hein, David W.

Abstract

Variation among the human population in the ability to acetylate drugs has been known since the observations on individual variations in isoniazid toxicity in the 1950s. The genetic basis for this was soon appreciated and has come to be known as the N-acetylation polymorphism. This chapter provides as background a description of some key studies that showed that acetylation was variable in the human population, that it is inherited, and the molecular basis for this phenomenon. Since accurate determination of acetylator phenotype is critical to testing a number of important hypotheses, including the link between disease risk and acetylator phenotype, limitations and potential problems with various methods of phenotype determination are discussed. Similarly, procedures and approaches for determination of NAT1 and NAT2 genotype are described. The final section brings phenotype and genotype together by examining the relationship between variant alleles and disease incidence. Increasingly, these studies have relied solely on the measurement of genotype, with the assumption that phenotype may be accurately deduced from genotype. There is a fairly wide degree of variability in the frequency of discordance between genotype and phenotype, however, especially when caffeine is used as a probe for phenotype determination. The potential consequences of this discordance are discussed. [ABSTRACT FROM AUTHOR]

Published
2005
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230. Heterocyclic amines reduce insulin-induced AKT phosphorylation and induce gluconeogenic gene expression in human hepatocytes.

Author

Walls, Kennedy M., Hong, Kyung U., and Hein, David W.

Subjects
*INSULIN receptors, *LIVER cells, *TYPE 2 diabetes, *GENE expression, *HUMAN genes, *AMINES
Abstract

Heterocyclic amines (HCAs) are well-known for their mutagenic properties. One of the major routes of human exposure is through consumption of cooked meat, as certain cooking methods favor formation of HCAs. Recent epidemiological studies reported significant associations between dietary HCA exposure and insulin resistance and type II diabetes. However, no previous studies have examined if HCAs, independent of meat consumption, contributes to pathogenesis of insulin resistance or metabolic disease. In the present study, we have assessed the effect of three HCAs commonly found in cooked meat (2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline [MeIQ], 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline [MeIQx], and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine [PhIP]) on insulin signaling and glucose production. HepG2 or cryopreserved human hepatocytes were treated with 0–50 μM of MeIQ, MeIQx, or PhIP for 3 days. Treatment of HepG2 cells and hepatocytes with MeIQ and MeIQx resulted in a significant reduction in insulin-induced AKT phosphorylation, suggesting that HCA exposure decreases hepatic insulin signaling. HCA treatment also led to significant increases in expression of gluconeogenic genes, G6PC and PCK1, in both HepG2 and cryopreserved human hepatocytes. Additionally, the level of phosphorylated FOXO1, a transcriptional regulator of gluconeogenesis, was significantly reduced by HCA treatment in hepatocytes. Importantly, HCA treatment of human hepatocytes led to increases in extracellular glucose level in the presence of gluconeogenic substrates, suggesting that HCAs induce hepatic glucose production. The current findings suggest that HCAs induce insulin resistance and promote hepatic glucose production in human hepatocytes. This implicates that exposure to HCAs may lead to the development of type II diabetes or metabolic syndrome. [ABSTRACT FROM AUTHOR]

Published
2023
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231. DNA Adduct Levels and Intestinal Lesions in Congenic Rapid and Slow Acetylator Syrian Hamsters Administered the Food Mutagens 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) or 2-Amino-3-methylimidazo[4,5-f]quinoline (IQ

Author

Steffensen, Inger-Lise, primary, Fretland, Adrian J., additional, Paulsen, Jan Erik, additional, Feng, Yi, additional, Eide, Tor Jacob, additional, Devanaboyina, Udaya-Sankar, additional, Hein, David W., additional, and Alexander, Jan, additional

Published
2000
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247. Influence of N‐acetyltransferase polymorphism in the N‐acetylation of asparagine and putrescine.

Author

Salazar‐Gonzalez, Raul A. and Hein, David W.

Abstract

R4723 --> 699.7 --> Amino acids play central roles in cancer progression beyond their function as building blocks for protein synthesis. Because of this, targeting amino acid acquisition and uptake has been proved to be a potential therapeutic strategy to limit cancer cell growth while leaving the normal tissues largely intact. Polyamines like Putrescine (Put) are low molecular weight, aliphatic polycations found in the cells of all living organisms. Recent findings have described that abundance of N‐acetylated Asparagine (Asp) and Put are highly correlated with N‐acetylation capacity of N‐acetyltransferase 1 (NAT1). Here we tested the N‐acetylation of Asp and Put by recombinant human NAT1 and NAT2 as well as the effect of N‐acetylation polymorphisms in the metabolism of these substrates. Using genetically engineered CHO cells expressing either NAT1*4, NAT1*14, NAT2*4 or NAT2*5B alleles, in vitro N‐acetylation activity reactions were quantified using HPLC. Our results show that Asp is metabolized by both NAT1 and NAT2; enzymatic activity was quantified at different time points up to 60 min, as well as, increasing concentrations of the cofactor AcCoA. Using 100 μM of AcCoA, the formation of N‐acetyl Asp was 1.7 ±0.32 nmoles Ac‐Asp/mg protein in the reference allele (NAT1*4); on the other hand, NAT1*14 (slow) allele produced 1.12 ±0.32 nmoles Ac‐Asp/mg protein (p< 0.01); increasing AcCoA to 300 μM resulted in an increase 3.98 ±0.58 and 2.93 ±0.62 nmoles Ac‐Asp/mg protein, respectively (p< 0.01), Finally, Increasing the availability of AcCoA to 1 mM, produced an N‐acetylation rate of 9.82 ±3.73 and 4.64 ±0.61 nmoles Ac‐Asp/mg protein (p< 0.001). For NAT2, in the presence of 100 μM of AcCoA, the reference allele (NAT2*4) produced 1.43 ±0.6, whereas NAT2*5B (slow) produced 1.05 ±0.19 nmoles Ac‐Asp/mg protein (p< 0.05). 300 μM of AcCoA increased the rate to 3.1 ±0.93 vs 2.4 ±0.52 nmoles Ac‐Asp/mg protein (p< 0.05). Finally, using 1 mM AcCoA, N‐acetylation increased to 7.23 ±2.69 vs 5.11 ±0.79 nmoles Ac‐Asp/mg protein (p< 0.01). Both NAT1 and NAT2 catalyzed the Put N‐acetylation. For NAT1 in the presence of 100 μM of AcCoA, we observed the formation of 0.19 ±0.03 nmoles Ac‐Put/mg protein in NAT1*4, and 0.108 ±0.02 nmoles Ac‐Put/mg protein in NAT1*14 allele (p< 0.05). Using 300 μM of AcCoA, 0.27 ±0.02 in NAT1*4 vs 0.14 ±0.3 nmoles Ac‐Put/mg protein in NAT1*14 (p< 0.05). Finally, 1 mM of AcCoA yielded 0.43 ±0.03 vs 0.23 ±0.03 nmoles Ac‐Put/mg protein, respectively (p< 0.05). Finally, for NAT2 and Put N‐acetylation, our results show that the reference allele produces 0.26 ±0.03 vs 0.16 ±0.04 nmoles Ac‐Put/mg protein in the slow (NAT2*5B) allele when we used 100 μM of AcCoa (p< 0.05), 0.3 ±0.03 and 0.22 ±0.02 nmoles Ac‐Put/mg protein respectively when we used 300 μM of AcCoA; and 0.4 ±0.03 vs 0.3 ±0.02 nmoles Ac‐Put/mg protein respectively when we used 1 mM AcCoA. In conclusion, these results show that NAT1 and NAT2 are capable of the N‐acetylation of endogenous compounds like Asparagine and Putrescine. Moreover, this metabolic reaction is dependent of the AcCoA present and influenced by the genetic polymorphisms. Future studies will help us understand the implications of the N‐acetylation of these compounds in cellular processes like cancer cell progression. [ABSTRACT FROM AUTHOR]

Published
2022
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