Inhibition of prostaglandin E2 catabolism and potentiation of hepatic prostaglandin E2 action in rat hepatocytes by inhibitors of oxidative metabolism.
Prostaglandin E2 (PGE2) can modulate the actions of a number of hormones in liver. PGE2 is rapidly metabolized in liver tissue, and thus alterations in the rate of PGE2 catabolism might exert a short-term influence on the concentration of PGE2 in liver. The present study examined the effects of inhibitors of oxidative metabolism on PGE2 catabolism and action in isolated rat hepatocytes. [3H]-PGE2 was metabolized to three major products by the hepatocyte system as assessed by reverse-phase high performance liquid chromatography. Metyrapone (5 mM), aminopyrine (5 mM), SKF-525A (20 microM) and alpha-naphthoflavone (20 microM) each inhibited the breakdown of [3H]-PGE2. The inhibition of oxidative metabolism by these compounds was not limited to action at cytochrome P-450, and metyrapone, aminopyrine and SKF-525A each was shown to inhibit [1-14C]-palmitate beta-oxidation in the hepatocyte system. To determine the contribution of beta-oxidation to the rapid catabolism of [3H]-PGE2, studies were performed using [1-14C]-PGE2 as substrate. Two major product peaks seen with [3H]-PGE2 as substrate lacked radioactivity when [1-14C]-PGE2 was the substrate, and thus these two products did not contain the 1-position carbon, consistent with their identity as beta-oxidation products. Furthermore, [1-14C]-PGE2 also yielded 14CO2 and a [14C]-PGE2 metabolite not seen with [3H]-PGE2. It was calculated that 60% of the rapid PGE2 inactivation in the hepatocyte system occurred via beta-oxidation. An additional, non-beta-oxidation, metyrapone-sensitive, pathway accounted for 26% of PGE2 disappearance. The effect of PGE2 to inhibit glucagon-stimulated glycogenolysis was potentiated when metyrapone was included in the incubation, consistent with increased survival of intact PGE2. In summary, PGE2 was rapidly inactivated by intact hepatocytes via oxidative metabolism, primarily beta-oxidation. Inhibition of prostaglandin catabolism can have short-term effects on PGE2 concentrations and result in potentiation of PGE2 effects on hepatic glucose metabolism.
Brass
E P
EP
Department of Medicine, University of Colorado School of Medicine, Denver.
Beyerinck
R A
RA
Garrity
M J
MJ
D000632:Aminopyrine / Q000494:pharmacology; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D015232:Dinoprostone; D005934:Glucagon / Q000494:pharmacology; D006003:Glycogen / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D010084:Oxidation-Reduction; D011335:Proadifen / Q000494:pharmacology; D011458:Prostaglandins E / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D001571:Benzoflavones; D011458:Prostaglandins E; D000632:Aminopyrine; C011512:alpha-naphthoflavone; D006003:Glycogen; D005934:Glucagon; D011335:Proadifen; D015232:Dinoprostone; D008797:Metyrapone