textCyclosporine 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.Pharmac
