IDENTIFICATION AND PARTIAL CHARACTERIZATION OF 2 STEROID 5-ALPHA-REDUCTASE ISOZYMES IN THE CANINE PROSTATE

BACKGROUND. The dog has been extensively used as an in vivo model to t est the pharmacokinetics and effects on pathological prostatic growth of 5 alpha-reductase inhibitors. However, no information is available on the existence or characteristics of canine 5 alpha-reductase isozym es. METHODS. The 5 alpha-reduction of testosterone is analyzed in dog prostatic homogenates. Three human-specific inhibitors are tested for their activity against dog 5 alpha-reductase. RESULTS. Two pH optima o f 5 alpha-reductase activity in dog prostatic homogenates are describe d, comparable to the pH optima of rat and human 5 alpha-reductase isoz ymes. Kinetic analysis of 5 alpha-reductase enzymatic activity at pH 7 .0 revealed isozymes with a low apparent affinity constant (K-m = 2.67 nM) and a high apparent affinity constant (K-m = 1.23 mu M). These ap parent affinity constants compare favorably to the human and rat isozy mes types II and I, respectively. The human type II inhibitor finaster ide selectively inhibited the low K-m isozyme, whereas the human type I inhibitor MK386 preferentially inhibited the high k(m), isozyme. The human type I inhibitor LY306089 was nonspecific for the dog isozymes. CONCLUSIONS. We postulate that the high and low K-m isozymes describe d here represent the dog type I and type II 5 alpha-reductase isozymes , respectively. (C) 1998 Wiley-Liss, Inc.