TY - JOUR
T1 - Characterization of UGTs active against SAHA and association between SAHA glucuronidation activity phenotype with UGT genotype
AU - Balliet, Renee M.
AU - Chen, Gang
AU - Gallagher, Caria J.
AU - Dellinger, Ryan W.
AU - Sun, Dongxiao
AU - Lazarusw, Philip
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2009/4/1
Y1 - 2009/4/1
N2 - Suberoylanilide hydroxamic acid (SAHA) is a histone deace-tylase 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 IAS and IAlO exhibited the highest overall activity against SAHA as determined by Fmax/KM (16 ± 6.5, 7.1 ± 2.2, 33 ± 6.3, and 24 ± 2.4 nLmin-,-|i,g UGT protein-1, respectively), with UGT2B17 exhibiting the lowest KM (300 jxmoI/L) against SAHA of any UGT in vitro. Whereas the UGTlA8p.Alal73Gly variant exhibited a 3-fold (P < 0.005) decrease in glucuronidation activity against SAHA compared with wild-type UGT1A8, the UGTlA8p.Cys277Tyr variant exhibited no detectable glucur-onidation activity; a similar lack of detectable glucuronidation activity was observed for the UGTlA10p.Glyl39Lys 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 75% (P < 0.002) increase in KM compared with HLMs from subjects homozygous for the wild-type VGT2B17H 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.
AB - Suberoylanilide hydroxamic acid (SAHA) is a histone deace-tylase 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 IAS and IAlO exhibited the highest overall activity against SAHA as determined by Fmax/KM (16 ± 6.5, 7.1 ± 2.2, 33 ± 6.3, and 24 ± 2.4 nLmin-,-|i,g UGT protein-1, respectively), with UGT2B17 exhibiting the lowest KM (300 jxmoI/L) against SAHA of any UGT in vitro. Whereas the UGTlA8p.Alal73Gly variant exhibited a 3-fold (P < 0.005) decrease in glucuronidation activity against SAHA compared with wild-type UGT1A8, the UGTlA8p.Cys277Tyr variant exhibited no detectable glucur-onidation activity; a similar lack of detectable glucuronidation activity was observed for the UGTlA10p.Glyl39Lys 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 75% (P < 0.002) increase in KM compared with HLMs from subjects homozygous for the wild-type VGT2B17H 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.
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U2 - 10.1158/0008-5472.CAN-08-4143
DO - 10.1158/0008-5472.CAN-08-4143
M3 - Article
C2 - 19318555
AN - SCOPUS:66149089601
VL - 69
SP - 2981
EP - 2989
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 7
ER -