Temporal effect of tamoxifen on cytochrome P450 side chain cleavage gene expression and steroid concentration in adult male rats.
Adult male rats when treated with 0.4 mg tamoxifen (tam)/kg per day for 90 days show reduced circulating testosterone (T) and LH. The present study was designed to have an in depth understanding of tam induced androgen reduction in adult male rats. Adult male rats were orally administered 0.4 mg tam/kg per day for 30, 60 or 90 days and the temporal effects on intratesticular concentrations of pregnenolone (P(5)), progesterone (P(4)), T, 5 alpha-dihydrotestosterone (5 alpha-DHT) and estradiol (E(2)) were estimated. Control group rats were fed saline. Serum hormonal profile of LH, FSH, T and E(2) was also followed on these days. Testicular levels of cytochrome P450 scc mRNA transcripts on 30, 60 and 90 days of treatment with the same dose were quantitated by biplex RT-PCR using beta Actin as internal control followed by analysis using GelPro Analysis software.A significant reduction in intratesticular P(5), P(4), T, 5 alpha-DHT and E(2) was observed from day 30 of treatment. The P450 scc gene expression in the testis was reduced during treatment period from day 60 of treatment. This study demonstrates for the first time that tam reduces testicular pregnenolone biosynthesis through an effect on cholesterol transport and downregulation of P450 scc gene expression. In confirmation of the observed estrogenic effects of tam in this study, it is suggested that E(2) may have a role in cholesterol transport and testicular pregnenolone biosynthesis at the level of cytochrome P450 scc as shown by us.
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Department of Neuroendocrinology, Institute for Research in Reproduction (ICMR), J.M. Street, Parel, Mumbai 400 012, India. priyankaparte@rediffmail.com
Balasinor
N
N
Gill-Sharma
M K
MK
Maitra
A
A
Juneja
H S
HS
D000284:Administration, Oral; D000728:Androgens / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D013196:Dihydrotestosterone / Q000378:metabolism; D015536:Down-Regulation; D004958:Estradiol / Q000097:blood; D004965:Estrogen Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D005640:Follicle Stimulating Hormone / Q000097:blood; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011284:Pregnenolone / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000493:pharmacokinetics / Q000494:pharmacology*; D013737:Testis / Q000187:drug effects* / Q000201:enzymology; D013739:Testosterone / Q000097:blood
D000728:Androgens; D017931:DNA Primers; D004965:Estrogen Antagonists; D012333:RNA, Messenger; D013196:Dihydrotestosterone; D013629:Tamoxifen; D013739:Testosterone; D011374:Progesterone; D004958:Estradiol; D011284:Pregnenolone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol