Inhibitors of the cytochrome P-450 enzymes block the secretagogue-induced release of corticotropin in mouse pituitary tumor cells.

A mouse pituitary tumor cell line (AtT-20) releases corticotropin (ACTH) in response to a number of secretagogues, including corticotropin-releasing factor (CRF), beta-adrenergic agents, N6,O2'-dibutyryladenosine 3',5'-cyclic monophosphate (Bt2 cAMP), and potassium. The stimulation of ACTH secretion induced by the secretagogues can be blocked by inhibitors of the enzymes that generate (phospholipase A2) and metabolize (lipoxygenase and epoxygenase) arachidonic acid. The phospholipase A2 blockers mepacrine and p-bromophenacylbromide inhibited the ACTH release induced by secretagogues. The lipoxygenase inhibitors nordihydroguaieretic acid, butylated hydroxytoluene, and icosatetraynoic acid abolished the ACTH secretion induced by secretagogues, whereas indomethacin, a cycloxygenase inhibitor, did not. Blockers of the cytochrome P-450 epoxygenase, such as SKF 525A and piperonyl butoxide, compounds that have different molecular structures, also suppressed secretagogue-induced ACTH release. These findings suggest that metabolites of arachidonic acid formed via the epoxygenase and/or the lipoxygenase pathway are involved in the stimulation of ACTH release caused by secretagogues.