Close Association of UGT1A9 IVS1+399C>T with UGT1A1*28, *6, or *60 Haplotype and Its Apparent Influence on 7-Ethyl-10-hydroxycamptothecin (SN-38) Glucuronidation in Japanese

@article{Saito2009CloseAO,
  title={Close Association of UGT1A9 IVS1+399C>T with UGT1A1*28, *6, or *60 Haplotype and Its Apparent Influence on 7-Ethyl-10-hydroxycamptothecin (SN-38) Glucuronidation in Japanese},
  author={Yoshiro Saito and Kimie Sai and Keiko Maekawa and Nahoko Kaniwa and Kuniaki Shirao and Tetsuya Hamaguchi and Noboru Yamamoto and Hideo Kunitoh and Yuichiro Ohe and Yasuhide Yamada and Tomohide Tamura and Teruhiko Yoshida and Hironobu Minami and Atsushi Ohtsu and Yasuhiro Matsumura and Nagahiro Saijo and Jun-ichi Sawada},
  journal={Drug Metabolism and Disposition},
  year={2009},
  volume={37},
  pages={272 - 276}
}
The anticancer prodrug, irinotecan, is converted to its active form 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxylesterases, and SN-38 is inactivated by UDP-glucuronosyltransferase (UGT)1A1-mediated glucuronidation. UGT1A9 also mediates this reaction. In a recent study, it was reported that the UGT1A9 IVS1+399 (I399)C>T polymorphism is associated with increased SN-38 glucuronidation both in vitro and in vivo. However, its role in UGT1A9 expression levels and activity is controversial. Thus… 

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References

SHOWING 1-10 OF 17 REFERENCES
THE NOVEL UGT1A9 INTRONIC I399 POLYMORPHISM APPEARS AS A PREDICTOR OF 7-ETHYL-10-HYDROXYCAMPTOTHECIN GLUCURONIDATION LEVELS IN THE LIVER
TLDR
Results indicate that UGT1A9 I399 and –118T9/10 may represent additional candidates in combination with UGT 1A1 promoter haplotypes for the prediction of SN-38 glucuronidation profile in vivo.
Influence of UGT1A9 intronic I399C>T polymorphism on SN-38 glucuronidation in Asian cancer patients
TLDR
This in vivo study supports the in vitro findings of Girard et al. and suggests that the UGT1A9 I399C>T variant may be an important glucuronidating allele affecting the pharmacokinetics of SN-38 andSN-38G in Asian cancer patients receiving irinotecan chemotherapy.
Common human UGT1A polymorphisms and the altered metabolism of irinotecan active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38).
TLDR
The data provide the evidence that molecular determinants of irinotecan response may include the UGT1A polymorphisms studied herein and common genetic variants of the hepatic UGT 1A9 isoenzyme yet to be described.
Glucuronidation of 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of irinotecan (CPT-11), by human UGT1A1 variants, G71R, P229Q, and Y486D.
TLDR
The SN-38 glucuronidation activity of Y486D was drastically reduced, whereas the reduction in the G71R and P229Q activities was fractional, and the decreased SN- 38 glucuronidated efficiency ratio of G71 R and P 229Q could be critical in combination with other polymorphisms in the UGT1A1 gene.
Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese: roles of UGT1A1*6 and *28
TLDR
The haplotypes significantly associated with reduced area under concentration curve ratios and neutropenia contained UGT1A1*6 or *28, and both of them should be genotyped before irinotecan is given to Japanese and probably other Asian patients.
Lack of Association between Common Polymorphisms in UGT1A9 and Gene Expression and Activity
TLDR
The data demonstrate that the common I399C>T and–118T9>10 polymorphisms do not explain interindividual variation in hepatic UGT1A9 activity and mRNA expression and are in complete LD in the donor liver samples the authors studied.
Identification of a defect in the UGT1A1 gene promoter and its association with hyperbilirubinemia.
TLDR
The results indicate that homozygosity and compound heterozygosity for mutations in the UGT1A1 gene promoter (T-3263G and A[TA](7)TAA) and/or exon 1 of the gene (G211A) could explain the hyperbilirubinemia seen in the majority of individuals with Gilbert's syndrome.
Influence of UGT1A7 and UGT1A9 Intronic I399 Genetic Polymorphisms on Mycophenolic Acid Pharmacokinetics in Japanese Renal Transplant Recipients
TLDR
There were no significant differences in MPA pharmacokinetics among UGT 1A7 or UGT1A9 intronic I399 genotype groups and polymorphisms do not contribute to interindividual differences in NLP.
Haplotype structures of the UGT1A gene complex in a Japanese population
TLDR
Important haplotypes and their linkages were identified among the UGT1A gene blocks (and segments), which should be considered in pharmacogenetic studies.
Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism?
TLDR
It is suggested that the unstable UGT1A1 polymorphism may serve to "fine-tune" the plasma bilirubin level within population groups, maintaining it at a high enough level to provide protection against oxidative damage, but at a level that is sufficiently low to prevent kernicterus in infants.
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