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Hormonal regulation of cytochrome P450 enzymes, cholesterol side-chain cleavage and 17 alpha-hydroxylase/C17-20 lyase in Leydig cells. 1990

A H Payne
Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor 48109-0278.

Testosterone biosynthesis in Leydig cells is dependent on two cytochrome P450 enzymes, cholesterol side-chain cleavage (P450scc) and 17 alpha-hydroxylase/C17-20 lyase (P450(17 alpha]. The expression of these two enzymes is differentially regulated by LH acting via its second messenger, cyclic adenosine 3',5'-monophosphate (cAMP), and by specific steroid hormones. P450scc is constitutively expressed in normal mouse Leydig cells and in MA-10 tumor Leydig cells. Chronic cAMP stimulation increases the steady state levels of P450scc mRNA and de novo P450scc protein synthesis. In contrast, cAMP is obligatory for de novo synthesis of P450(17 alpha) in normal mouse Leydig cells; P450(17 alpha) synthesis ceases in the absence of luteinizing hormone or cAMP. MA-10 tumor Leydig cells do not express P450(17 alpha) even after treatment with cAMP. The amount of P450(17 alpha) in Leydig cells is negatively regulated by testosterone acting by two distinct mechanisms. At low concentrations, testosterone acts via the androgen receptor to repress cAMP-induced synthesis of P450(17 alpha), whereas at high concentrations this steroid increases the rate of degradation of the enzyme by an oxygen-mediated mechanism. Both constitutive and cAMP-induced synthesis of P450scc protein and steady state levels of mRNA are modulated by glucocorticoids. In normal mouse Leydig cells, glucocorticoids repress P450scc synthesis and steady state levels of P450scc mRNA, whereas glucocorticoids stimulate P450scc synthesis and levels of P450scc mRNA in the tumor Leydig cells.(ABSTRACT TRUNCATED AT 250 WORDS)

UI MeSH Term Description Entries
D007985 Leydig Cells Steroid-producing cells in the interstitial tissue of the TESTIS. They are under the regulation of PITUITARY HORMONES; LUTEINIZING HORMONE; or interstitial cell-stimulating hormone. TESTOSTERONE is the major androgen (ANDROGENS) produced. Interstitial Cells, Testicular,Leydig Cell,Testicular Interstitial Cell,Testicular Interstitial Cells,Cell, Leydig,Cell, Testicular Interstitial,Cells, Leydig,Cells, Testicular Interstitial,Interstitial Cell, Testicular
D007986 Luteinizing Hormone A major gonadotropin secreted by the adenohypophysis (PITUITARY GLAND, ANTERIOR). Luteinizing hormone regulates steroid production by the interstitial cells of the TESTIS and the OVARY. The preovulatory LUTEINIZING HORMONE surge in females induces OVULATION, and subsequent LUTEINIZATION of the follicle. LUTEINIZING HORMONE consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH and FSH), but the beta subunit is unique and confers its biological specificity. ICSH (Interstitial Cell Stimulating Hormone),Interstitial Cell-Stimulating Hormone,LH (Luteinizing Hormone),Lutropin,Luteoziman,Luteozyman,Hormone, Interstitial Cell-Stimulating,Hormone, Luteinizing,Interstitial Cell Stimulating Hormone
D008297 Male Males
D002786 Cholesterol Side-Chain Cleavage Enzyme A mitochondrial cytochrome P450 enzyme that catalyzes the side-chain cleavage of C27 cholesterol to C21 pregnenolone in the presence of molecular oxygen and NADPH-FERRIHEMOPROTEIN REDUCTASE. This enzyme, encoded by CYP11A1 gene, catalyzes the breakage between C20 and C22 which is the initial and rate-limiting step in the biosynthesis of various gonadal and adrenal steroid hormones. CYP11A1,Cholesterol Desmolase,Cholesterol Monooxygenase (Side-Chain-Cleaving),Cytochrome P-450 CYP11A1,Cytochrome P-450(scc),20,22-Desmolase,CYP 11A1,Cytochrome P450 11A1,Cytochrome P450scc,20,22 Desmolase,Cholesterol Side Chain Cleavage Enzyme,Cytochrome P 450 CYP11A1
D003577 Cytochrome P-450 Enzyme System A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism. Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D006063 Chorionic Gonadotropin A gonadotropic glycoprotein hormone produced primarily by the PLACENTA. Similar to the pituitary LUTEINIZING HORMONE in structure and function, chorionic gonadotropin is involved in maintaining the CORPUS LUTEUM during pregnancy. CG consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is virtually identical to the alpha subunits of the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity (CHORIONIC GONADOTROPIN, BETA SUBUNIT, HUMAN). Chorionic Gonadotropin, Human,HCG (Human Chorionic Gonadotropin),Biogonadil,Choriogonadotropin,Choriogonin,Chorulon,Gonabion,Human Chorionic Gonadotropin,Pregnyl,Gonadotropin, Chorionic,Gonadotropin, Human Chorionic
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000242 Cyclic AMP An adenine nucleotide containing one phosphate group which is esterified to both the 3'- and 5'-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and ACTH. Adenosine Cyclic 3',5'-Monophosphate,Adenosine Cyclic 3,5 Monophosphate,Adenosine Cyclic Monophosphate,Adenosine Cyclic-3',5'-Monophosphate,Cyclic AMP, (R)-Isomer,Cyclic AMP, Disodium Salt,Cyclic AMP, Monoammonium Salt,Cyclic AMP, Monopotassium Salt,Cyclic AMP, Monosodium Salt,Cyclic AMP, Sodium Salt,3',5'-Monophosphate, Adenosine Cyclic,AMP, Cyclic,Adenosine Cyclic 3',5' Monophosphate,Cyclic 3',5'-Monophosphate, Adenosine,Cyclic Monophosphate, Adenosine,Cyclic-3',5'-Monophosphate, Adenosine,Monophosphate, Adenosine Cyclic
D013250 Steroid Hydroxylases Cytochrome P-450 monooxygenases (MIXED FUNCTION OXYGENASES) that are important in steroid biosynthesis and metabolism. Steroid Hydroxylase,Steroid Monooxygenases,Hydroxylase, Steroid,Hydroxylases, Steroid,Monooxygenases, Steroid
D013254 Steroid 17-alpha-Hydroxylase A microsomal cytochrome P450 enzyme that catalyzes the 17-alpha-hydroxylation of progesterone or pregnenolone and subsequent cleavage of the residual two carbons at C17 in the presence of molecular oxygen and NADPH-FERRIHEMOPROTEIN REDUCTASE. This enzyme, encoded by CYP17 gene, generates precursors for glucocorticoid, androgen, and estrogen synthesis. Defects in CYP17 gene cause congenital adrenal hyperplasia (ADRENAL HYPERPLASIA, CONGENITAL) and abnormal sexual differentiation. 17 alpha-Hydroxylase,17,20-Lyase,CYP17,Cytochrome P-450(17 alpha),P450(c17),Steroid 17 alpha-Monooxygenase,Steroid 17-Hydroxylase,Steroid 17-Monooxygenase,17 alpha-Hydroxylase Cytochrome P-450,17 alpha-Hydroxyprogesterone Aldolase,17,20-Desmolase,Cytochrome P-450(17-alpha),Cytochrome P450(17 alpha),Hydroxyprogesterone Aldolase,Steroid 17 alpha-Hydroxylase,Steroid-17-Hydroxylase,17 alpha Hydroxylase,17 alpha Hydroxylase Cytochrome P 450,17 alpha Hydroxyprogesterone Aldolase,17 alpha-Hydroxylase, Steroid,17 alpha-Monooxygenase, Steroid,17,20 Desmolase,17,20 Lyase,17-Hydroxylase, Steroid,17-Monooxygenase, Steroid,17-alpha-Hydroxylase, Steroid,Aldolase, 17 alpha-Hydroxyprogesterone,Aldolase, Hydroxyprogesterone,Steroid 17 Hydroxylase,Steroid 17 Monooxygenase,Steroid 17 alpha Hydroxylase,Steroid 17 alpha Monooxygenase,alpha-Hydroxyprogesterone Aldolase, 17,alpha-Monooxygenase, Steroid 17

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