This Article Full Text Full Text (PDF) All Versions of this Article: 0008-5472.CAN-08-4143v1 69/7/2981    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Balliet, R. M. Articles by Lazarus, P. Search for Related Content PubMed PubMed Citation Articles by Balliet, R. M. Articles by Lazarus, P.

Characterization of UGTs Active against SAHA and Association between SAHA Glucuronidation Activity Phenotype with UGT Genotype

¹ Cancer Control and Population Sciences, Penn State Cancer Institute, and Departments of ² Pharmacology and ³ Public Health Sciences, Penn State University College of Medicine, Hershey, Pennsylvania

Requests for reprints: Philip Lazarus, Division of Population Sciences and Cancer Prevention, Penn State Cancer Institute, Department of Pharmacology, MC-H069, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033. Phone: 717-531-5734; Fax: 717-531-0480; E-mail: plazarus{at}psu.edu.

Key Words: UGT • glucuronidation • SAHA • HDAC inhibitor • polymorphism

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. [Cancer Res 2009;69(7):2981–9]