Absence of hepatic p-nitrophenol UDP-glucuronosyltransferase induction by spironolactone in male rats: possible involvement of testosterone

Abstract

This study was performed to determine whether the lack of spironolactone induction of hepatic p-nitrophenol UDP-glucuronosyltransferase in male rats could be attributed to a presumed interaction between spironolactone and testosterone. The effect of spironolactone was evaluated in four experimental groups: normal females, normal males, castrated males, and castrated males that received testosterone. Enzyme activity was measured in native microsomes and in microsomes activated with UDP-N-acetylglucosamine or Triton X-100. When the nucleotide was included in the incubations, it was observed that enzyme activity in castrated male rats decreased to values approaching those obtained in normal females. Treatment of castrated animals with testosterone enhanced enzyme activity so that no significant difference existed between this group and normal males. This suggests that testosterone may act as an endogenous inducer of hepatic p-nitrophenol glucuronidation. It was also found that only females and castrated males showed an increase in enzyme activity in response to spironolactone treatment. Thus, the absence of an additive effect of endogenous or exogenous testosterone and spironolactone on UDP-glucuronosyltransferase activity suggests that these compounds could share a common induction mechanism, which appears to reach its maximal capacity in male rats. Possible explanations of this observation are discussed. From the analysis of enzyme activity in native and Triton X-100 activated microsomes, it can be postulated that spironolactone enzyme induction in female and castrated male rats could be attributed to an enhancement in the transferase synthesis rather than to an alteration of the membrane environment.Key words: UDP-glucuronosytransferase, spironolactone, enzyme induction, testosterone, p-nitrophenol.