Dr. N‐Acetylation Polymorphism and Diabetes Mellitus among Saudi Arabians

El-Yazigi, Adnan; Johansen, Klaus; Raines, Dale A.; Døssing, Martin

doi:10.1002/j.1552-4604.1992.tb04636.x

Cited by 11 publications

(8 citation statements)

References 12 publications

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“…Populations numbered from 1 to 13 were analyzed in this study: (1) Bakola Pygmies, (2) Baka Pygmies, (3) Ateke Bantus, (4) Somali, (5) Morrocans, (6) Ashkenazi Jews, (7) Sardinians, (8) Swedes, (9) Saami, (10) Turkmen, (11) Gujarati, (12) Thai, and (13) Chinese. Numbers 14 to 36 refer to a reviewed population: (14) Yorubas (Jeyakumar and French 1981), (15) Zimbabweans (Nhachi 1988), (16) South Africans (Hodgkin et al 1979), 17Libyans (Karim et al 1981), (18) Saudi Arabians (El-Yazigi et al 1992), (19) Emiratis (Woolhouse et al 1997), 20Iranians (Sardas et al 1993), (21) Jordanians (Irshaid et al 1992), (22) Turkmen (Bozkurt et al 1990), (23) Greeks (Asprodini et al 1998), (24) Germans (Cascorbi et al 1995), (25) Russians (Lil'in et al 1984), (26) Pakistanis (Saleem et al 1989), (27) Bangladeshi (Zaid et al 2004), (28) Thai (Kukongviriyapan et al 1984), (29) Malaysians (Ong et al 1990), (30) Chinese (Zhao et al 2000), (31) Koreans (Lee et al 2002), (32) Japanese (Hashiguchi and Ebihara 1992), (33) Papua New Guineans (Hombhanje 1990), (34) Australian Aborigines (Ilett et al 1993), (35) Eskimos (Eidus et al 1974), and (36) Amerindians (Jorge-Nebert et al 2002).…”

Section: Figurementioning

confidence: 99%

Deciphering the Ancient and Complex Evolutionary History of Human Arylamine N-Acetyltransferase Genes

Patin

Barreiro

Sabeti

et al. 2006

The American Journal of Human Genetics

124

117

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The human N-acetyltransferase genes NAT1 and NAT2 encode two phase-II enzymes that metabolize various drugs and carcinogens. Functional variability at these genes has been associated with adverse drug reactions and cancer susceptibility. Mutations in NAT2 leading to the so-called slow-acetylation phenotype reach high frequencies worldwide, which questions the significance of altered acetylation in human adaptation. To investigate the role of population history and natural selection in shaping NATs variation, we characterized genetic diversity through the resequencing and genotyping of NAT1, NAT2, and the pseudogene NATP in a collection of 13 different populations with distinct ethnic backgrounds and demographic pasts. This combined study design allowed us to define a detailed map of linkage disequilibrium of the NATs region as well as to perform a number of sequence-based neutrality tests and the long-range haplotype (LRH) test. Our data revealed distinctive patterns of variability for the two genes: the reduced diversity observed at NAT1 is consistent with the action of purifying selection, whereas NAT2 functional variation contributes to high levels of diversity. In addition, the LRH test identified a particular NAT2 haplotype (NAT2*5B) under recent positive selection in western/central Eurasians. This haplotype harbors the mutation 341T-->C and encodes the "slowest-acetylator" NAT2 enzyme, suggesting a general selective advantage for the slow-acetylator phenotype. Interestingly, the NAT2*5B haplotype, which seems to have conferred a selective advantage during the past approximately 6,500 years, exhibits today the strongest association with susceptibility to bladder cancer and adverse drug reactions. On the whole, the patterns observed for NAT2 well illustrate how geographically and temporally fluctuating xenobiotic environments may have influenced not only our genome variability but also our present-day susceptibility to disease.

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Section: Figurementioning

confidence: 99%

Deciphering the Ancient and Complex Evolutionary History of Human Arylamine N-Acetyltransferase Genes

Patin

Barreiro

Sabeti

et al. 2006

The American Journal of Human Genetics

124

117

View full text Add to dashboard Cite

show abstract

“…This comes as no sur prise since this enzyme has been employed to deter mine the ace ty la tion phe no type of the indi vid ual (i.e., fast or slow ace ty la tor), which is known to be influ enced by the genetic con sti tu tion of the indi vidual and by vari ous dis eases other than those of the liver (i.e., dia be tes mel li tus, blad der can cer, etc.). 28,29 Although there was no sig nifi cant dif fer ence in the uri nary molar ratio of 1U/1X that reflects the activ ity of XO 4,21,22,30 between LD patients and con trols, the mean value observed in the patients was twice that in the con trol sub ject (Table II). This sug gests no or a slight link between XO and LD.…”

Section: Discussionmentioning

confidence: 91%

Salivary Clearance and Urinary Metabolic Pattern of Caffeine in Healthy Children and in Pediatric Patients with Hepatocellular Diseases

El-Yazigi¹,

Shabib²,

Al‐Rawithi³

et al. 1999

The Journal of Clinical Pharma

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Measurement of salivary clearance and urinary metabolites of caffeine is an excellent noninvasive tool for assessing liver function, particularly the activity of cytochrome P4501A2 (CYP1A2), N-acetyltransferase (NAT), and xanthine oxidase (XO). This study was undertaken to measure the clearance of caffeine using saliva as a biological fluid and to assess the activities of the above-mentioned enzymes in healthy children and pediatric patients with liver diseases using urinary molar ratios of different caffeine metabolites. The well-established two-sample saliva approach was used to measure the clearance of caffeine in nine pediatric patients with liver diseases (LD) and in nine healthy children. The caffeine metabolites were also measured in the urine of these subjects by high-performance liquid chromatography, and urinary molar ratios of 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methylxanthine (1X), 1-methyluric acid (1U), and 1,7-dimethyluric acid (17U) were employed to estimate the activities of CYP1A2, NAT, and XO. The caffeine salivary clearance and the percentage of the dose excreted in the form of various metabolites were significantly (p < 0.035) smaller in the LD patients than those in healthy children. The urinary molar ratio of [AFMU + 1U + 1X]/17U, which reflects the activity of CYP1A2, was also significantly (p < 0.0005) reduced in these patients. However, there were no significant differences between the two groups in the ratios of AFMU/1X and 1U/1X, which estimate the activities of NAT and XO, respectively. In conclusion, the data obtained suggest that liver disease in pediatric subjects significantly reduces the salivary clearance of caffeine and the activity of cytochrome P4501A2, but it has no impact on the activities of NAT and XO.

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“…The majority of the studies investigating the acetylator phenotype in type 2 DM also suggested a possible excess of rapid acetylators [45,46,[51][52][53][54], but this difference was less striking than that reported in phenotyping studies of type I DM previously cited, and it was not found in Arabian populations [55][56][57]. On the contrary, Agúndez et al [58], in their genotype analysis of 111 patients with type 2 DM, found no relationship between NAT2 polymorphism and type 2 DM.…”

Section: Diabetes Mellitus (Dm)mentioning

confidence: 90%

Influence of Polymorphic N-Acetyltransferases on Non-Malignant Spontaneous Disorders and on Response to Drugs

2008

CDM

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Polymorphic N-acetyl transferases (NAT) 1 and 2 are involved in detoxification of xenobiotic arylamines and hydralazines. These common environmental chemicals may be related to the pathogenesis of many spontaneous disorders, mainly malignancies, but also disimmune or degenerative diseases, for which a polygenic predisposition has been suggested. Hence, polymorphic NAT genes (NAT2 has been the most studied one) may be low-penetrance risk genes for some of these disorders. Although a relation of risk may be definitely discarded for systemic lupus erythematosus (SLE), inflammatory bowel disease and endometriosis, more research is needed for rheumatoid arthritis, Parkinson's, Alzheimer's, Behçet's and periodontal diseases , as current results are inconclusive but suggest a possible relation with NAT2 polymorphism. In diabetes mellitus the possible relation with the rapid phenotype may be due to acquired metabolic changes and more genotyping studies are needed. NAT2 slow metabolizers are more prone to the side effects of polymorphically acetylated drugs, as is the SLE-like syndrome induced by hydralazine and procainamide, the side effects due to sulphasalazine and the skin rash secondary to many sulphonamides. Future research should be based on well-designed studies, with adequate sample sizes and homogeneous recruitment criteria, to obviate the proliferation of small studies that are time- and resource-consuming without offering definite answers.

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Dr. N‐Acetylation Polymorphism and Diabetes Mellitus among Saudi Arabians

Cited by 11 publications

References 12 publications

Deciphering the Ancient and Complex Evolutionary History of Human Arylamine N-Acetyltransferase Genes

Deciphering the Ancient and Complex Evolutionary History of Human Arylamine N-Acetyltransferase Genes

Salivary Clearance and Urinary Metabolic Pattern of Caffeine in Healthy Children and in Pediatric Patients with Hepatocellular Diseases

Influence of Polymorphic N-Acetyltransferases on Non-Malignant Spontaneous Disorders and on Response to Drugs

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