Decreased cortisol secretion by adrenal glands perfused with the P-glycoprotein inhibitor valspodar and mitotane or doxorubicin

The aim of this study was to investigate the role of P-glycoprotein (P-gp) in the adrenal gland. It has been presumed that P-gp, rather than being inv olved in physiological cortisol secretion, plays a role in protecting the a drenacortical cells from xenobiotics. To explore this a study was performed on perfused bovine adrenal glands. Individual experimental groups were per fused with either a selective P-gp blocker (valspodar) alone, with a xenobi otic (mitotane or doxorubicin) alone or with both valspodar and a xenobioti c. The cumulative amounts of cortisol secreted in each individual group wer e calculated and the two-sample t-test was used to compare the mean values of cumulative amounts. The mean value of cortisol secreted from the group o f adrenals perfused with the P-gp blocker was not significantly different f rom that of the control group. Treatment with either mitotane or doxorubici n decreased the amount of cortisol secreted but not significantly when comp ared to the amount of cortisol secreted in basal conditions. However, treat ment with the P-gp blocker valspodar in addition to either mitotane or doxo rubicin significantly decreased cortisol secreted compared to the amount of cortisol secreted by the glands treated with either mitotane (p=0.009) or doxorubicin (p=0.017) alone. The regressive changes discovered in all exper imental groups were most prominent when valspodar was used with either mito tane or doxorubicin. We found that P-gp blockade increases by xenobiotic (m itotane and doxorubicin)-induced damage of adrenocortical cells, which poin ts to a role of P-gp in the protection of adrenal gland from xenobiotics. [ (C) 2000 Lippincott Williams & Wilkins.].