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.
Lee
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QP
Department of Pharmacology, School of Medicine, University of Washington, Seattle 98195.
Juchau
M R
MR
D000818:Animals; D046508:Culture Techniques; D000242:Cyclic AMP / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000201:enzymology; D005934:Glucagon / Q000494:pharmacology*; D008797:Metyrapone / Q000494:pharmacology; D009712:Nucleotides, Cyclic / Q000494:pharmacology; D010078:Oxazines / Q000032:analysis / Q000378:metabolism*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D065607:Cytochrome P-450 Enzyme Inhibitors; D009712:Nucleotides, Cyclic; D010078:Oxazines; D010726:Phosphodiesterase Inhibitors; C044943:pentoxyresorufin; D005934:Glucagon; D003577:Cytochrome P-450 Enzyme System; D000242:Cyclic AMP; D010088:Oxidoreductases; C063849:benzyloxyphenoxazone debenzylase; D019362:Cytochrome P-450 CYP2B1; D008797:Metyrapone