Calcium-mediated inhibition of glucuronide production by epinephrine in the perfused rat liver.
Rates of production of p-nitrophenyl glucuronide by isolated perfused livers from fed or fasted phenobarbital-treated rats were estimated by monitoring the concentration of glucuronide in the effluent perfusate. Infusion of epinephrine decreased the steady state level of p-nitrophenyl glucuronide by about 39% (half-maximal inhibition at approximately 5 microM). This result was unexpected because epinephrine activated glycogenolysis and elevated hepatic UDP-glucuronic acid contents. The effect of epinephrine can be attributed to its interaction with alpha-adrenergic receptors, since the inhibition of glucuronide production by epinephrine was reversed by an alpha-antagonist (phentolamine) but not by a beta-antagonist, propranolol. Since alpha-adrenergic agonists increase the cytosolic free calcium concentration, we investigated the possibility that the decrease in glucuronide production elicited by epinephrine was mediated by calcium. Removal of calcium from the perfusion fluid diminished the inhibition of glucuronide production by epinephrine, while increasing extracellular calcium from 0 to 150 microM restored the inhibition in a dose-dependent manner. In the presence of extracellular calcium, glucuronide production was inhibited by the addition of the calcium ionophore A23187 or angiotensin II, a hormone which increases cytosolic calcium. Concentrations of ionized calcium comparable to physiological intracellular levels (0.1-2 microM) increased microsomal beta-glucuronidase activity by 50 to 100% but had no effect on microsomal glucuronosyl-transferases . These results indicate that activation of hepatic alpha-adrenergic receptors increases cytosolic calcium which stimulates microsomal beta-glucuronidase activity. This decreases net glucuronide formation by the liver. In support of this hypothesis, rates of glucuronide production were unaffected by epinephrine in perfused livers from beta-glucuronidase-deficient C3H/HeJ mice.
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D004837:Epinephrine / Q000494:pharmacology*; D005260:Female; D005934:Glucagon / Q000494:pharmacology; D005965:Glucuronates / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D009596:Nitrophenols / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains
D005965:Glucuronates; D009596:Nitrophenols; C002730:4-nitrophenylglucuronide; D003994:Bucladesine; D005934:Glucagon; D005966:Glucuronidase; D002118:Calcium; C024836:4-nitrophenol; D004837:Epinephrine