Selective suppression of rat hepatic microsomal activity during chronic cyclosporine nephrotoxicity

Lane J. Brunner, William M. Bennett, Dennis R. Koop

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24 Scopus citations


Cyclosporine is an immunosuppressant that undergoes extensive hepatic biotransformation to hydroxylated and demethylated metabolites. At present, the CYP3A gene family is thought to be the primary enzyme system responsible for cyclosporine metabolism. The effect of chronic cyclosporine therapy on the suppression of drug metabolism was studied in male and female rats maintained on a low-salt diet. After 28 days of subcutaneous cyclosporine dosing 15 mg/kg, cyclosporine-treated rats had significant renal dysfunction as compared with gender-matched control rats. Creatinine clearance in male cyclosporine-treated rats was reduced by 47% (P < .01) as compared with male controls. Female rats demonstrated a 38% (P < .01) decrease in creatinine clearance as a result of chronic cyclosporine therapy. Despite similar nephrotoxicity, female rats had whole blood cyclosporine levels 48% (P < .01) less than male rats. Immunoblot analysis of hepatic microsomal proteins indicated that chronic cyclosporine treatment decreased the protein levels of P450 3A2 in male rats. This loss was paralleled by reduced production of 6β- hydroxytestosterone, the primary product of P450 3A activity, by hepatic microsomes from cyclosporine-treated male rats by 76% (P < .001). In addition, cyclosporine treatment of male rats also reduced the formation of 2α-hydroxytestosterone and 16α-hydroxytestosterone by 81% (P < .01) and 84% (P < .001), respectively. At the end of the study period, steroid 5α- reductase activity in control male rats was only 4% (P < .001) of female counterparts; however, cyclosporine treatment increased steroid 5α-reductase activity in male rats to 79% (P < .001) of female values. These alterations in testosterone metabolism are consistent with the suppression of the predominately male-associated P450 3A2, P450 2C11 and P450 2C13 isoforms. Levels of 6α-hydroxytestosterone and 7α-hydroxytestosterone were not statistically different between rat groups. Taken together, the steady-state blood levels and metabolism studies suggest that, after chronic cyclosporine treatment, isoforms other than those from the CYP3A family or unidentified members of the CYP3A family are likely responsible for cyclosporine metabolism.

Original languageEnglish (US)
Pages (from-to)1710-1718
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - Jun 1996
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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