Effect of a diphenylethylenediamine platinum complex on steroidogenesis in rats.
Although less cytotoxic, the new platinum complex [meso-1,2-bis(2,6-difluoro-4-hydroxyphenyl)-ethylenediamine]sulfatopl atinum (II) (2) is equipotent to cisplatin (1) in the oestrogen-dependent MXT mammary tumour of the mouse. As this may be due to oestrogen level-lowering properties, we compared the effect of 1 and 2 on steroidogenesis in the rat. A single dose of 1 and 2 (20 mumol/kg s.c.) decreased plasma testosterone level in male rats by 90% (1, day 3) and 80% (2, day 7). Luteinizing hormone level remained unchanged in intact and in ovariectomized rats. The activities of the following testicular enzymes were decreased (day 7): cholesterol side-chain cleavage enzyme (1: 33%; 2: 36%), 3 beta-hydroxysteroid dehydrogenase/delta 4,delta 5-isomerase (1: 31%; 2: 48%) and 17 alpha-hydroxylase/17,20-lyase (1: 21%; 2: 15%). Testicular microsomal cytochrome P450 content was also diminished (1: 60%; 2: 49%, day 7). Corticosterone level in plasma and biosynthesis in adrenal explants was not affected, indicating the selectivity of action at the gonadal level. In vitro, neither 1 nor 2 (2 and 20 microM) influenced binding of human chorionic gonadotropin to testis interstitial cells during an observation period up to 21 h. These results suggest that 1 and 2 act at the gonadal level by inhibiting the expression of the steroidogenic enzymes. They do not, however, inactivate the luteinizing hormone receptor.
Sergejew
T F
TF
Fachrichtung 12.1 Pharmazeutische Chemie, Universität des Saarlandes, Saarbrücken, Germany.
Hartmann
R W
RW
D015096:3-Hydroxysteroid Dehydrogenases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity; D006063:Chorionic Gonadotropin / Q000378:metabolism; D002945:Cisplatin / Q000031:analogs & derivatives / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005029:Ethylenediamines / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism; D008297:Male; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D010052:Ovariectomy; D010984:Platinum / Q000494:pharmacology* / Q000633:toxicity; D011388:Prolactin / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011974:Receptors, LH / Q000187:drug effects / Q000378:metabolism; D013256:Steroids / Q000378:metabolism*; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism
C101587:(1,2-bis(2,6-difluoro-4-hydroxyphenyl)ethylenediamine)sulfatoplatinum(II); D000970:Antineoplastic Agents; D006063:Chorionic Gonadotropin; D005029:Ethylenediamines; D009944:Organoplatinum Compounds; D011974:Receptors, LH; D013256:Steroids; D013739:Testosterone; D010984:Platinum; D011388:Prolactin; D007986:Luteinizing Hormone; D003577:Cytochrome P-450 Enzyme System; D015096:3-Hydroxysteroid Dehydrogenases; D002945:Cisplatin; D003345:Corticosterone