Tin-protoporphyrin: a potent inhibitor of hemoprotein-dependent steroidogenesis in rat adrenals and testes.
The present investigation provides evidence of the ability of Sn-protoporphyrin to cause striking alterations in adrenal and testicular cytochrome P-450-dependent steroidogenesis and defines the potential of this metalloporphyrin to serve as a cellular toxin. Sn-protoporphyrin is currently used on an experimental basis for treatment of hyperbilirubinemias in humans, including newborn infants. Specifically, in the adrenals of rats treated with a moderate regimen of Sn-protoporphyrin (two doses of 50 mumol/kg, s.c.), marked decreases of 60 to 70% in the microsomal 21 alpha-hydroxylase and the mitochondrial 11 beta-hydroxylase activities were observed after 7 days. Concomitant with these decreases was a significant depression in the adrenal mitochondrial cytochrome P-450 content and a notable reduction (approximately 30%) in serum corticosterone levels. Similarly, in the testes, significant decreases in the microsomal and mitochondrial cytochrome P-450 contents and the microsomal 17 alpha-hydroxylase activity were observed. Serum testosterone level, however, was not decreased, reflecting an absence of decrease in side chain cleavage activity. Metalloporphyrin caused a striking decrease of 65 to 80% in the microsomal heme oxygenase activity in the testes and the adrenals, as well as significant reductions in NADPH-cytochrome P-450 reductase activity of the organs. The decrease in heme oxygenase activity, however, as suggested by Western immunoblotting, apparently resulted, to a large extent, from the loss of enzyme protein integrity rather than a competitive inhibition of activity. At the transcript level, Northern blot analysis using a full length rat testis cDNA probe for heme oxygenase-2 mRNA indicated that Sn-protoporphyrin treatment did not decrease the amount of message for either of the heme oxygenase-2 transcripts (1.3 and 1.9 Kb).(ABSTRACT TRUNCATED AT 250 WORDS)
Maines
M D
MD
University of Rochester School of Medicine, Department of Biophysics, New York.
Trakshel
G M
GM
D000311:Adrenal Glands / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004247:DNA / Q000235:genetics; D015342:DNA Probes; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006420:Hemeproteins / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D008861:Microsomes / Q000201:enzymology; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013154:Spleen / Q000201:enzymology; D013252:Steroid 11-beta-Hydroxylase / Q000378:metabolism; D013255:Steroid 21-Hydroxylase / Q000378:metabolism; D013256:Steroids / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013737:Testis / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism
D015342:DNA Probes; D006420:Hemeproteins; D008665:Metalloporphyrins; D011524:Protoporphyrins; D013256:Steroids; D012313:RNA; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; C032628:tin protoporphyrin IX; D013255:Steroid 21-Hydroxylase; D006419:Heme Oxygenase (Decyclizing); D013252:Steroid 11-beta-Hydroxylase; D009251:NADPH-Ferrihemoprotein Reductase