Barbiturates modulate the activity of the pituitary 3 alpha-hydroxysteroid oxidoreductases and inhibit their production of 3 alpha,5 alpha-tetrahydroprogesterone.
The effects of sodium phenobarbital and sodium barbital on the activity of the particulate and cytosolic 5 alpha-dihydroprogesterone 3 alpha-hydroxysteroid oxidoreductases (3 alpha-HSORs) of female rat anterior pituitary were investigated. By altering the 3 alpha-HSOR catalyzed conversion of 5 alpha-dihydroprogesterone (5 alpha-DHP) to 3 alpha,5 alpha-tetrahydroprogesterone (3 alpha,5 alpha-THP), these barbiturates could influence the in situ production of 3 alpha,5 alpha-THP. 3 alpha,5 alpha-THP has potent barbiturate-like effects on brain GABAA receptors. Both phenobarbital and 3 alpha,5 alpha-THP can affect gonadotropin release in female rats. In vitro incubations of each 3 alpha-HSOR activity were assayed in the presence of sodium phenobarbital (0.1 to 10.0 mM) or sodium barbital (1.0 to 10.0 mM). Since both 3 alpha-HSOR activities catalyze the reversible oxidoreduction of 5 alpha-DHP and 3 alpha,5 alpha-THP, we examined the effect of these barbiturates not only on the conversion of 5 alpha-DHP to 3 alpha,5 alpha-THP (reductive reaction) but also on the "back conversion" of 3 alpha,5 alpha-THP to 5 alpha-DHP (oxidative reaction). The results indicate that both phenobarbital and, to a lesser extent barbital, significantly affected the activities of the two 3 alpha-HSORs in both reductive and oxidative directions. In the reductive direction, phenobarbital inhibited the activity (33%) of both cytosolic and particulate enzymes which would presumably decrease the levels of 3 alpha,5 alpha-THP. In the oxidative direction, a pattern of stimulation was observed (20 to 100%). Thus, this stimulatory effect on the oxidative conversion of 3 alpha,5 alpha-THP to 5 alpha-DHP, which would presumably also decrease 3 alpha,5 alpha-THP levels, appears correlated with the inhibitory effect of these barbiturates on the reductive conversion of 5 alpha-DHP to 3 alpha,5 alpha-THP. Sodium barbital exhibited somewhat similar effects. These changes suggest that barbiturates can lower 3 alpha,5 alpha-THP levels in the anterior pituitary. The results also suggest the possibility that lowered 3 alpha,5 alpha-THP levels may be involved, at least in part, in the reduction of gonadotropin release by barbiturates.
Karavolas
H J
HJ
Department of Biomolecular Chemistry, University of Wisconsin-Madison 53706.
Hodges
D R
DR
D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); D000818:Animals; D001462:Barbital / Q000494:pharmacology*; D004790:Enzyme Induction; D005260:Female; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology*; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000201:enzymology*; D011280:Pregnanolone / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000494:pharmacology
D012965:Sodium Chloride; D001462:Barbital; D011280:Pregnanolone; D015096:3-Hydroxysteroid Dehydrogenases; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); D010634:Phenobarbital