Characterization of UGTs active against SAHA and association between SAHA glucuronidation activity phenotype with UGT genotype. Other Scholarly Work

Balliet, Renee M, Chen, Gang, Gallagher, Carla J et al. (2009). Characterization of UGTs active against SAHA and association between SAHA glucuronidation activity phenotype with UGT genotype. . 69(7), 2981-2989. 10.1158/0008-5472.can-08-4143

cited authors

  • Balliet, Renee M; Chen, Gang; Gallagher, Carla J; Dellinger, Ryan W; Sun, Dongxiao; Lazarus, Philip

fiu authors

abstract

  • Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor used in the treatment of cutaneous T-cell lymphoma and in clinical trials for treatment of multiple other cancers. A major mode of SAHA metabolism is by glucuronidation via the UDP-glucuronosyltransferase (UGT) family of enzymes. To characterize the UGTs active against SAHA, homogenates from HEK293 cell lines overexpressing UGT wild-type or variant UGT were used. The hepatic UGTs 2B17 and 1A9 and the extrahepatic UGTs 1A8 and 1A10 exhibited the highest overall activity against SAHA as determined by V(max)/K(M) (16+/-6.5, 7.1+/-2.2, 33+/-6.3, and 24+/-2.4 nL x min(-1) x microg UGT protein(-1), respectively), with UGT2B17 exhibiting the lowest K(M) (300 micromol/L) against SAHA of any UGT in vitro. Whereas the UGT1A8p.Ala173Gly variant exhibited a 3-fold (P<0.005) decrease in glucuronidation activity against SAHA compared with wild-type UGT1A8, the UGT1A8p.Cys277Tyr variant exhibited no detectable glucuronidation activity; a similar lack of detectable glucuronidation activity was observed for the UGT1A10p.Gly139Lys variant. To analyze the effects of the UGT2B17 gene deletion variant (UGT2B17*2) on SAHA glucuronidation phenotype, human liver microsomes (HLM) were analyzed for glucuronidation activity against SAHA and compared with UGT2B17 genotype. HLM from subjects homozygous for UGT2B17*2 exhibited a 45% (P<0.01) decrease in glucuronidation activity and a 75% (P<0.002) increase in K(M) compared with HLMs from subjects homozygous for the wild-type UGT2B17*1 allele. Overall, these results suggest that several UGTs play an important role in the metabolism of SAHA and that UGT2B17-null individuals could potentially exhibit altered SAHA clearance rates with differences in overall response.

publication date

  • April 1, 2009

keywords

  • Cell Line
  • Enzyme Inhibitors
  • Glucuronosyltransferase
  • Humans
  • Hydroxamic Acids
  • Mutagenesis, Site-Directed
  • Mutation, Missense
  • Phenotype
  • Polymorphism, Genetic
  • Vorinostat

Digital Object Identifier (DOI)

Medium

  • Print-Electronic

start page

  • 2981

end page

  • 2989

volume

  • 69

issue

  • 7