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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

The Effect of Allelic Variation in Aldo-Keto Reductase 1C2 on the in Vitro Metabolism of Dihydrotestosterone

Division of Pharmaceutics and Biopharmaceutics (R.H.T., K.W.R.) and Division of Biomolecular and Pharmaceutical Chemistry (R.E.R.), Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada; and Department of Zoology, Faculty of Science, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada (T.A.G.)

Aldo-keto reductase (AKR) 1C2 is a human, cytosolic enzyme that has an important role in the deactivation of the potent androgen dihydrotestosterone (DHT). AKR1C2 can regulate the extent and duration of activation of the androgen receptor by catalyzing the reduction of DHT to the less potent receptor ligand 3-diol. In this study, we functionally characterize in vitro the effect of 11 naturally occurring nonsynonymous single nucleotide polymorphisms on the ability of AKR1C2 to reduce DHT to 3-diol. The wild-type and variant enzymes were expressed using a transfected insect cell system, and their kinetic activities were measured using both a specific fluorogenic probe and DHT as substrates. This functional characterization demonstrates that several variant AKR1C2 proteins have significantly reduced or altered reductase activities as shown by their measured kinetic parameters. Data from our two separate in vitro studies revealed significant reductions in V_max for two variants (F46Y and L172Q) and significantly lower apparent K_m values for three variants (L172Q, K185E, and R258C) compared with the wild type. These results provide evidence that several naturally occurring nonsynonymous single nucleotide polymorphisms in AKR1C2 result in reduced enzyme activities. These variant AKR1C2 alleles may represent one factor involved in the variable degradation of DHT in vivo.

Address correspondence to: Dr. K. Wayne Riggs, Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z3. E-mail: riggskw{at}interchange.ubc.ca

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