Mechanisms of glucagon-induced increases in rates of cytochrome P450-dependent pentoxyphenoxazone O-depentylation in cultured rat conceptuses.

Inclusions of glucagon (1.0 or 2.0 microM, final concentrations) in the media of cultured whole rat conceptuses resulted in concentration-dependent increases in measured rates of O-depentylation of pentoxyphenoxazone in cell-free preparations of conceptal tissues. Enzymic activities were assayed 24 h after initial exposure of the conceptuses to glucagon on day 10 of gestation. Glucagon elicited increases in tissue levels of cAMP that were parallel to those produced by 3-isobutyl-1-methylxanthine over the same time period. Tissue cAMP levels were maximal after 2 h, rapidly returned to control levels and were also equal to background levels in controls after the 24 h culture period. Dibutyryl cAMP, 3-isobutyl-1-methylxanthine, theophylline, and RO201724, a cAMP-selective phosphodiesterase inhibitor, each produced 75 to 100% increases in O-dealkylase activity. Dibutyryl cGMP and two phosphodiesterase inhibitors, enoximone (cGMP-inhibited) and zaprinast (cGMP-specific), each failed to produce statistically significant increases in O-depentylase activity. The O-depentylase was tentatively identified as a conceptus-specific P450 cytochrome that is synthesized predominantly in tissues of the visceral yolk sac. The results indicated that glucagon may upregulate a unique, xenobiotic-biotransforming P450(s) via a long-term mechanism(s) specifically involving tissue cAMP.