Functional characterization of human xanthine oxidase allelic variants

Kudo, Mutsumi; Moteki, Toshiko; Sasaki, Takuma; Konno, Yumiko; Ujiie, Shuta; Onose, Akemi; Mizugaki, Michinao; Ishikawa, Masaaki; Hiratsuka, Masahiro

doi:10.1097/fpc.0b013e3282f55e2e

Cited by 83 publications

(73 citation statements)

References 37 publications

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“…38 Variation in TPMT and XO activity across ethnic groups have been described which may affect the metabolism of thiopurines. 39,40 However, there is no published information about any difference in the frequency of ''selective MMP shunters'' or response to the allopurinol-thiopurine combination therapy across populations.…”

Section: Discussionmentioning

confidence: 99%

Role of Allopurinol in Optimizing Thiopurine Therapy in Patients with Autoimmune Hepatitis: A Review

Deswal

Srivastava

2017

Journal of Clinical and Experimental Hepatology

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Autoimmune hepatitis (AIH) is a chronic immune mediated liver disease characterized by elevated transaminases, hyper gammaglobulinemia, presence of autoantibodies and interface hepatitis in the absence of a known etiology of liver disease. Thiopurines (azathioprine [AZA]/6-mercaptopurine [6MP]) and steroids remain the first line of treatment of AIH in both children and adults. However, a small proportion of AIH patients are either non-responders or develop side effects with AZA. The metabolism of AZA is complex and mediated by multiple enzymes. After absorption and getting converted to 6MP, it is converted to 6-thiouric acid, 6-methyl mercaptopurine (6MMP) and 6-thioguanine (6TG) by different enzymes. Elevated 6MMP levels are associated with hepatotoxicity and also poor efficacy due to simultaneous lower levels of 6TG, which is the active drug metabolite related to both efficacy and myelosuppression. Allopurinol, a xanthine oxidase inhibitor shifts the metabolism of AZA away from 6MMP toward 6TG. This combination of allopurinol with reduced dose of AZA is an alternative to more expensive and toxic second line therapy to induce remission in patients with AIH. This article discusses the mechanism of action of allopurinol in inducing response to AZA, reviews the published literature on this combination therapy and gives guidelines on the use of allopurinol in patients with AIH. ( J CLIN EXP HEPATOL 2017;7:55-62)

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Section: Discussionmentioning

confidence: 99%

Role of Allopurinol in Optimizing Thiopurine Therapy in Patients with Autoimmune Hepatitis: A Review

Deswal

Srivastava

2017

Journal of Clinical and Experimental Hepatology

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“…Because of the rarity of functional genetic variations in the XO gene [20], sex and cigarette smoking have been widely investigated as a possible determinants of XO activity. Most of the previous studies did not observe any correlation between sex and enzyme activity [19,21,22,43,44].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies, using radiochemical assay [13] or caffeine test [11,14,18,19], showed that XO activity differs among individuals. Known functional genetic variations in the XO gene are rare [20]. Although environmental factors seem to be responsible for the described variability [15,17,19], it is generally accepted that cigarette smoking does not affect XO activity [11,19,21].…”

Section: Introductionmentioning

confidence: 99%

In vivo evaluation of CYP2A6 and xanthine oxidase enzyme activities in the Serbian population

Djordjević

Carrillo

Gervasini

et al. 2010

Eur J Clin Pharmacol

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Purpose The main aim of the study was to investigate the distribution of cytochrome P450 2A6 (CYP2A6) and xanthine oxidase (XO) enzyme activities in the Serbian population. Secondly, we tested the influence of genetics (CYP2A6 polymorphism), sex, and cigarette smoking on both enzymes. Methods One hundred forty healthy Serbian volunteers were genotyped for common CYP2A6 alleles. In 100 of them, CYP2A6 and XO activities were determined by the urinary 17U/17X and 1U/(1U+1X) ratios, respectively, after oral administration of 100 mg caffeine as a probe. Results A 21-fold variation in the 17U/17X ratio was observed (range: 0.49-10.28, mean=1.65, 95% CI: 1.49-1.83). The urinary 1U/(1U+1X) ratios displayed four-fold variation, ranging from 0.17 to 0.71 (mean=0.43, 95% CI: 0.41-0.45). CYP2A6 alleles *1A, *1B1, *9, *4 and *1B1x2 were found with frequencies of 0.579, 0.307, 0.082, 0.029, and 0.004 respectively. CYP2A6*5 was not detected. CYP2A6 genotype influenced interindividual variability in CYP2A6 enzyme activity (P=0.04). Cigarette smoking inhibited CYP2A6 enzyme activity (P=0.02), but had no effect on activity of XO (P=0.16).There was no significant difference between men and women in terms of CYP2A6 or XO activity. Conclusions Serbs displayed interindividual variations in CYP2A6 activity. CYP2A6 genotype and cigarette smoking, but not sex, influenced CYP2A6 enzyme activity. Unimodal distribution of XO enzyme activity in Serbs implies the absence of subjects with low enzyme activity in this population. XO activity is not influenced by sex or cigarette smoking.

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“…Kudo et al 16 defined variations in a group of 96 Japanese. Several polymorphisms were defined, which correlated with individual differences in XO enzyme activity.…”

Section: Implications For the Asia-pacific Regionmentioning

confidence: 99%

Azathioprine and allopurinol: A two‐edged interaction

Gearry

Day

Barclay

et al. 2010

J of Gastro and Hepatol

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Functional characterization of human xanthine oxidase allelic variants

Abstract: These results suggest that several single nucleotide polymorphisms in the XO gene are involved in individual variations in XO activity. In addition, such findings will be useful to identify xanthinuria patients.

Cited by 83 publications

References 37 publications

Role of Allopurinol in Optimizing Thiopurine Therapy in Patients with Autoimmune Hepatitis: A Review

Role of Allopurinol in Optimizing Thiopurine Therapy in Patients with Autoimmune Hepatitis: A Review

In vivo evaluation of CYP2A6 and xanthine oxidase enzyme activities in the Serbian population

Azathioprine and allopurinol: A two‐edged interaction

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