Rapid down-regulation of testicular androgen biosynthesis at increased environmental temperature is due to cytochrome P450c17 (CYP17) thermolability in Leydig cells, but not in endoplasmic reticulum membranes.
To identify possible molecular targets in moderate heat-induced, short-term derangements of rat testicular endocrine function, rates of androgen and precursor biosynthesis and key enzyme concentrations were compared at 38 degrees C (normal body core temperature) and 31 degrees C (normal scrotal temperature) in three in-vitro models of decreasing complexity and increasing specificity. In purified Leydig cells and similarly in decapsulated testes, gross testosterone secretion was by 20% higher at 38 degrees C under basal conditions and during the initial phase of stimulation with hCG or cAMP; longer (> 1 hour) exposure to the elevated temperature resulted in a marked decrease (52% after 3 hours) of testosterone response to hCG or cAMP as compared to the corresponding rates at 31 degrees C. This phenomenon was neither due to the development of hormone resistance at the receptor level nor to restricted cholesterol supply and turnover nor to increased testosterone accumulation. Whereas mitochondrial CYP11A (cytochrome P450cscc: cholesterol monooxygenase) was absolutely temperature-insensitive in all systems tested, CYP17 (cytochrome P450c17: steroid-17 alpha-monooxygenase/C17, 20-aldolase) in the smooth endoplasmic reticulum responded with a 57% loss in whole testes and 39% loss in purified Leydig cells upon a 3-hour temperature elevation from 31 degrees C to 38 degrees C. In contrast, CYP17 was stable (4% loss) when tested directly in microsomal membranes. It is concluded that CYP17, but not CYP11A, is very sensitive towards even moderate elevation of environmental temperature, and that this apparent lability is not an intrinsic property of the enzyme protein but rather mediated by heat-activated intracellular factors.
Kühn-Velten
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Department of Obstetrics and Gynecology, Heinrich Heine University, Düsseldorf, Germany.
D000728:Androgens / Q000096:biosynthesis*; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004355:Drug Stability; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D006706:Homeostasis; D006358:Hot Temperature; D007425:Intracellular Membranes / Q000201:enzymology; D007700:Kinetics; D007985:Leydig Cells / Q000201:enzymology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012741:Sexual Maturation; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism*; D013737:Testis / Q000201:enzymology*; D013816:Thermodynamics
D000728:Androgens; D003577:Cytochrome P-450 Enzyme System; D013254:Steroid 17-alpha-Hydroxylase