Effects of heme oxygenase isozymes on Leydig cells steroidogenesis.
In the present study, we demonstrate the expression of heme oxygenase (HO) isozymes, HO-1 and HO-2 (listed as HMOX1 and HMOX2 in the MGI Database), in MA-10 Leydig tumor cells and its effect on steroidogenesis. The well-known HO inducer, hemin, increased both HO-1 and HO-2 protein levels and HO-specific activity. Induction of HO by hemin inhibited basal, hCG-, and dibutyryl cAMP (db-cAMP)-induced steroidogenesis in a reversible way. When we studied the effect of HO isozymes along the steroid synthesis, we found that steroidogenic acute regulatory protein levels were decreased, and the conversion of cholesterol to pregnenolone was inhibited by hemin treatment, with no changes in the content of cholesterol side-chain cleavage enzyme (P450scc). hCG and db-cAMP also stimulated the expression of HO-1 and HO-2, and HO enzymatic activity in MA-10 cells. Basal and hCG-stimulated testosterone synthesis was also inhibited by hemin in rat normal Leydig cells. Taken together, these results suggest that: i) at least one of HO products (presumably carbon monoxide) inhibits cholesterol transport to the inner mitochondrial membrane and Leydig cell steroidogenesis by binding to the heme group of the cytochrome P450 enzymes, in a similar way as we described for nitric oxide, and ii) hCG stimulation results in the induction of an antioxidant enzymatic system (HO) acting as a cytoprotective mechanism in Leydig cells, as already demonstrated in the adrenal gland.
Piotrkowski
Barbara
B
Laboratory of Molecular Endocrinology and Signal Transduction, Institute of Biology and Experimental Medicine-CONICET, Vuelta de Obligado 2490, CP 1428 Buenos Aires, Argentina.
Monzón
Casandra M
CM
Pagotto
Romina M
RM
Reche
Cecilia G
CG
Besio
Marcos
M
Cymeryng
Cora B
CB
Pignataro
Omar P
OP
D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism; D045744:Cell Line, Tumor; D006063:Chorionic Gonadotropin / Q000378:metabolism; D003995:Dibutyryl Cyclic GMP; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D007985:Leydig Cells / Q000201:enzymology*; D008297:Male; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000096:biosynthesis*; D000098682:Steroidogenic Acute Regulatory Protein
D006063:Chorionic Gonadotropin; D007527:Isoenzymes; D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; D003995:Dibutyryl Cyclic GMP; D013739:Testosterone; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2