The role of endocrine factors in the alteration of cytochromes P450 by cyclosporine

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Date

2004

Authors

Lu, Shirley Kwan

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Abstract

Cyclosporine is an immunosuppressant whose side effects include suppressing cytochrome P450 (P450) levels and activity in the liver. This effect may be one of the underlying causes in the difficulties in relating cyclosporine blood levels with efficacy and toxicity. Growth hormone (GH) is known to pretranslationally regulate P450 expression, while prolactin can interact directly with cyclosporine as an immunomodulator. Thus, the suppression of P450 by cyclosporine may involve GH or prolactin as intermediates. In order to address these hypotheses, the effect of exogenous GH and prolactin, separately and in combination with cyclosporine, on P450 3A1/2 (CYP3A1/2) and 2C11 (CYP2C11) was investigated. In addition, the direct effects of cyclosporine on GH-related cellular signaling factors were examined in vitro. Results from in vivo studies revealed that cyclosporine does not alter GH levels as a mediating event in suppressing P450s, although GH is a dominating factor over cyclosporine in determining hepatic P450 expression. The additive suppression in P450 activity seen with the concomitant administration of cyclosporine and GH suggests that changes in hormonal status is likely to be one of many factors that is responsible for the lack of a clear association between cyclosporine dose and toxicity. In the context of prolactin as a mediating factor in the suppression of P450 by cyclosporine, bromocriptine caused a significant suppression of CYP3A1/2 and CYP2C11 protein and activity levels when it was administered alone and in combination with cyclosporine. While cyclosporine and bromocriptine, separately, can significantly alter the fate of hepatic P450 enzymes, the suppression is likely not due to an alteration in prolactin levels. In vitro studies indicate that P450s are differentially modulated by cyclosporine. While CYP3A1/2 is decreased at specific concentrations, CYP2C11 is increased in a dose-dependent manner. This increase in CYP2C11 correlated with increases in Stat5b binding activity, which initiates transcription of P450 genes in the nucleus. Taken together, these studies indicate that while cyclosporine does not suppress P450 enzymes by altering GH or prolactin levels, one of the avenues of suppression is through modifying intracellular signaling elements.

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