UGT1A7 polymorphisms in chronic pancreatitis: an example of genotyping pitfalls

Morsche, R.H.M. te; Drenth, Joost P.H.; Truninger, Kaspar; Schulz, H.-U.; Kage, Andreas; Landt, Olfert; Verlaan, Mariette; Rosendahl, Jonas; Mácek, M; Jansen, J. B. M. J.; Witt, Heiko

doi:10.1038/sj.tpj.6500443

Cited by 19 publications

(7 citation statements)

References 26 publications

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“…[41] Likewise, a large pharmacokinetic variability was expected to exist among individuals with different UGT1A1, UGT1A7, UGT1A8 and UGT1A9 genotypes. [42][43][44][45] In clinical practice, the patients with UGT1A1*28 not only are prone to suffer Gilbert syndrome, but have an impaired capacity for glucuronidation of SN-38. [42] Besides, UGT1A7*3 allele has been reported as a significant risk factor for pancreatic disorders.…”

Section: High-affinitymentioning

confidence: 99%

Characterization of metabolic activity, isozyme contribution and species differences of bavachin, and identification of efflux transporters for bavachin-O-glucuronide in HeLa1A1 cells

Yang

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives Bavachin is a bioactive natural flavonoid with oestrogen-like activity. Here, we aimed to investigate its metabolic and disposal fates involving in CYPs, UGTs and efflux transporters. Methods Phase I metabolism and glucuronidation were performed by human liver microsomes (HLM). Reaction phenotyping and activity correlation analysis were performed to identify the main CYP and UGT isozymes. Chemical inhibition and gene knock-down approaches were employed to explore the function of BCRP and MRPs. Key findings Five phase I metabolites (M1-M5) and three glucuronides (G1-G3) were identified. The CL int values for M4 and G1 by HLM were 127.99 and 1159.07 μl/min per mg, respectively. Reaction phenotyping results suggested CYP1A1 (208.85 μl/min per mg) and CYP2C9 (107.51 μl/min per mg), and UGT1A1 (697.19 μl/min per mg), UGT1A7 (535.78 μl/min per mg), UGT1A8 (247.72 μl/min per mg) and UGT1A9 (783.68 μl/min per mg) all participated in the metabolism of bavachin. In addition, activity correlation analysis also supported the results above. Furthermore, the metabolism exhibited marked species differences, and rabbits were the appropriate model animals. Moreover, MRP4 was identified as the main contributor based on chemical inhibition and gene silencing approaches. Conclusions CYP1A1 and CYP2C9, UGT1A1, UGT1A7, UGT1A8 and UGT1A9, and MRP4 all played important roles in the metabolism and disposition of bavachin.

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Section: High-affinitymentioning

confidence: 99%

Characterization of metabolic activity, isozyme contribution and species differences of bavachin, and identification of efflux transporters for bavachin-O-glucuronide in HeLa1A1 cells

Yang

et al. 2020

Journal of Pharmacy and Pharmacology

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“…Indeed, epidemiologic studies have provided evidence of a significant association between an allelic variant UGT1A7*3 and carcinogenesis (Ockenga et al, 2003;Chen et al, 2006). However, controversial results showing no relationship between UGT1A7*3 and cancer risk have also been reported (Verlaan et al, 2005;te Morsche et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Alteration of the Function of the UDP-Glucuronosyltransferase 1A Subfamily by Cytochrome P450 3A4: Different Susceptibility for UGT Isoforms and UGT1A1/7 Variants

et al. 2013

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Functional protein-protein interactions between UDPglucuronosyltransferase (UGT)1A isoforms and cytochrome P450 (CYP)3A4 were studied. To this end, UGT1A-catalyzed glucuronidation was assayed in Sf-9 cells that simultaneously expressed UGT and CYP3A4. In the kinetics of UGT1A6-catalyzed glucuronidation of serotonin, both Michaelis constant (K m ) and maximal velocity (V max ) were increased by CYP3A4. When CYP3A4 was coexpressed with either UGT1A1 or 1A7, the V max for the glucuronidation of the irinotecan metabolite (SN-38) was significantly increased. S 50 and K m both which are the substrate concentration giving 0.5 V max were little affected by simultaneous expression of CYP3A4. This study also examined the catalytic properties of the allelic variants of UGT1A1 and 1A7 and their effects on the interaction with CYP3A4. Although the UGT1A1-catalyzing activity of 4-methylumbelliferone glucuronidation was reduced in its variant, UGT1A1*6, the coexpression of CYP3A4 restored the impaired function to a level comparable with the wild type. Similarly, simultaneous expression of CYP3A4 increased the V max of UGT1A7*1 (wild type) and *2 (N129K and R131K), whereas the same was not observed in UGT1A7*3 (N129K, R131K, and W208R). In the kinetics involving different concentrations of UDPglucuronic acid (UDP-GlcUA), the K m for UDP-GlcUA was significantly higher for UGT1A7*2 and *3 than *1. The K m of UGT1A7*1 and *3 was increased by CYP3A4, whereas *2 did not exhibit any such change. These results suggest that (1) CYP3A4 changes the catalytic function of the UGT1A subfamily in a UGT isoformspecific manner and (2) nonsynonymous mutations in UGT1A7*3 reduce not only the ability of UGT to use UDP-GlcUA but also CYP3A4-mediated enhancement of catalytic activity, whereas CYP3A4 is able to restore the UGT1A1*6 function.

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“…Vogel et al described that the UGT1A7 * 3 allele, exhibiting reduced carcinogen detoxification activity, was significantly associated with proximal gastrointestinal cancer (10). This last study was probably flawed since the overrepresentation of the UGT1A7 * 3 allele was due to PCR-dependent bias (11,12). There is a gap in the literature with respect to UGT polymorphisms and the risk for EC.…”

Section: Introductionmentioning

confidence: 99%

High enzyme activity UGT1A1 or low activity UGT1A8 and UGT2B4 genotypes increase esophageal cancer risk

et al. 2012

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Abstract. Esophageal cancer (EC) has a globally increasing incidence with poor curative treatment options and survival rates. Environmental and dietary factors have crucial roles in esophageal carcinogenesis. Polymorphisms in the UGT genes, a superfamily of enzymes essential for the detoxification of carcinogens, may alter enzyme activity and subsequently may play a role in EC etiology. Rather than solely establishing differences in genotype distribution, we investigated whether functional polymorphisms in UGT genes that can predict enzyme activity in vivo, may influence EC risk. A case-control study including 351 Caucasian EC patients and 592 Caucasian controls was conducted and polymorphisms in seven UGT genes were determined, using the polymerase chain reaction. On the basis of allelic in vitro enzyme activity measurements, genotypes were categorized according to their predicted in vivo enzyme activity into high, medium and low categories. Predicted enzyme activity groups were combined and compared between patients and controls. The UGT1A1 and UGT1A8 predicted high enzyme activity genotypes were significantly more (OR=1.62; 95% CI, 1.02-2.56) and less frequent (OR=0.36; 95% CI, 0.15-0.84) among patients with esophageal squamous cell carcinoma (ESCC), respectively. High (OR=0.42; 95% CI, 0.22-0.84) and medium (OR=0.25; 95% CI, 0.12-0.52) activity UGT2B4 genotypes were significantly less often present in ESCC patients. No association was detected between UGT genotypes and esophageal adenocarcinoma (EAC) risk. Polymorphisms in UGT genes, resulting in altered enzyme activity genotypes, do not seem modifiers of EAC risk. However, the predicted high activity UGT1A1 genotype, associated with low serum levels of the antioxidant bilirubin, was associated with an increased ESCC risk. The UGT1A8 and UGT2B4 genotypes associated with decreased predicted enzyme activities, were significantly associated with an increased risk of ESCC, probably by a decreased detoxification of carcinogens.

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UGT1A7 polymorphisms in chronic pancreatitis: an example of genotyping pitfalls

Cited by 19 publications

References 26 publications

Characterization of metabolic activity, isozyme contribution and species differences of bavachin, and identification of efflux transporters for bavachin-O-glucuronide in HeLa1A1 cells

Characterization of metabolic activity, isozyme contribution and species differences of bavachin, and identification of efflux transporters for bavachin-O-glucuronide in HeLa1A1 cells

Alteration of the Function of the UDP-Glucuronosyltransferase 1A Subfamily by Cytochrome P450 3A4: Different Susceptibility for UGT Isoforms and UGT1A1/7 Variants

High enzyme activity UGT1A1 or low activity UGT1A8 and UGT2B4 genotypes increase esophageal cancer risk

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