Comparative effects of etomidate and its fluoro analogue, R 8110 on testicular, adrenal and ovarian steroid biosynthesis.
The effects, of etomidate and of its fluoro analogue, R 8110, on adrenal, testicular and ovarian steroid biosynthesis were compared using cultures of guinea-pig adrenal, rat adrenal capsular, rat testicular and rat ovarian granulosa cells. At a concentration of 100 nM, etomidate inhibited the adrenal 11-hydroxylation of glucocorticoid and mineralocorticoid biosyntheses, producing a decrease in cortisol and corticosterone and an accumulation of 11-deoxycortisol and 11-deoxycorticosterone in guinea-pig adrenal and rat capsular adrenal cell suspensions, respectively. At higher concentrations (greater than 10(-6) M), etomidate also inhibited ovarian oestradiol production, testicular androgen formation and ovarian progesterone synthesis. The latter action suggests an effect on ovarian aromatase, on testicular 17 alpha/17,20-lyase activities and finally on cholesterol side-chain cleavage. The fluoro analogue of etomidate, R 8110, was ten times less potent as an inhibitor of 11-hydroxylation and affected progesterone formation only slightly in adrenal cell suspensions. Testosterone production was less affected by R 8110 than by etomidate. The increase of progestins suggests that the 17 alpha/17,20-lyase activities are the most sensitive testicular enzymatic reactions to R 8110. For inhibition of ovarian oestradiol production, R 8110 was twenty times more potent than etomidate.
De Coster
R
R
Janssen Research Foundation, Beerse, Belgium.
Wouters
W
W
Beerens
D
D
Haelterman
C
C
Doolaege
R
R
Goeminne
N
N
Krekels
M
M
D000305:Adrenal Cortex Hormones / Q000096:biosynthesis*; D000311:Adrenal Glands / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D005045:Etomidate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D012739:Gonadal Steroid Hormones / Q000096:biosynthesis*; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D006168:Guinea Pigs; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats
D000305:Adrenal Cortex Hormones; D012739:Gonadal Steroid Hormones; D006993:Hypnotics and Sedatives; C052803:R 8110; D005045:Etomidate