Journal article
Characterization of UGTs Active against SAHA and Association between SAHA Glucuronidation Activity Phenotype with UGT Genotype
Cancer research (Chicago, Ill.), Vol.69(7), pp.2981-2989
04/01/2009
Handle:
https://hdl.handle.net/2376/108634
PMCID: PMC2694132
PMID: 19318555
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·min
−1.
μg UGT protein
−1
, respectively), with UGT2B17 exhibiting the lowest K
M
(300 μmol/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.
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Details
- Title
- Characterization of UGTs Active against SAHA and Association between SAHA Glucuronidation Activity Phenotype with UGT Genotype
- Creators
- Renee M Balliet - Cancer Control and Population Sciences, Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PennsylvaniaGang Chen - Cancer Control and Population Sciences, Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PennsylvaniaCarla J Gallagher - Cancer Control and Population Sciences, Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PennsylvaniaRyan W Dellinger - Cancer Control and Population Sciences, Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PennsylvaniaDongxiao Sun - Cancer Control and Population Sciences, Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PennsylvaniaPhilip Lazarus - Cancer Control and Population Sciences, Penn State Cancer Institute, Penn State University College of Medicine, Hershey, Pennsylvania
- Publication Details
- Cancer research (Chicago, Ill.), Vol.69(7), pp.2981-2989
- Academic Unit
- Pharmaceutical Sciences, Department of
- Identifiers
- 99900547402401842
- Language
- English
- Resource Type
- Journal article