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ROLE OF CYCLIC AMP AND ENZYME ACTIVITIES IN THE INHIBITION OF PROGESTERONE SECRETION BY AMPHETAMINE.
Tsai, Shiow-Chwen1, Wang, Paulus2, 1 2
ABSTRACT- The present study is to examine whether acute administration of amphetamine (AMPH) modifies release of progesterone and activities of steroidogenic enzymes in luteal cells. Rat luteal cells were cultured with or without human chorionic gonadotropin (hCG, 0.5 IU/ml), cholera toxin (an activator of Gs protein, 1 g/ml), 8-bromo-adenosine 3′:5′-cyclic monophosphate (8-Br-cAMP, a membrane permeable analog of cAMP, 0.1 mM), or steroidogenic precursors (0.001~10 M) including 25-hydroxycholesterol (25-OH-C), and pregnenolone in the presence or absence of AMPH at 37 °C for 2 h. At the end of incubation, the medium was collected and measured for progesterone and pregnenolone by RIA. Progesterone production was increased by hCG (p<0.01). Administration of AMPH (0.01~1 M) dose-dependently decreased the basal and hCG-stimulated release of progesterone by rat luteal cells. Progesterone was increased by cholera toxin, 8-Br-cAMP, and pregnenolone. However, AMPH at 1 M decreased the release of progesterone in response to cholera toxin by 28±2%, and to 8-Br-cAMP by 8±1%. Pregnenolone at 10 M abolished the inhibitory effect of AMPH. 25-OH-C at 0.1 M and 10 M increased pregnenolone release by 37±10% (p<0.05) and 56±12% (p<0.01), AMPH at 1 M decreased 25-OH-C-increased pregnenolone release by 12~24% (p<0.05). In the presence of trilostane (10 M), an inhibitor of 3-hydroxysteroid dehydrogenase, increased pregnenolone accumulation by 273±20%. Trilostane did not alter AMPH effect on 25-OH-C-increased pregnenolone release. These results suggest that AMPH inhibits progesterone production by acting directly on the luteal cells via the mechanism involving the decrease of (1) the action of cAMP, and (2) the enzyme activity of cytochrome P450 side chain cleavage for producing pregnenolone from cholesterol.
KEY WORDS: amphetamine, progesterone, cAMP, cytochrome P450 side chain cleavage
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