CYP11A1 is a mitochondrial enzyme that catalyzes theconversion of cholesterol to pregnenolone. This represents thefirst reaction in the process of steroidogenesis in all steroidhormone-producing mammalian tissues () (). Low expression ofCYP11A1 may cause steroid biosynthesis disorders ().
In the testosterone biosynthetic pathway, DHEA is converted to testosterone in the testis; in the beta-estradiol biosynthetic pathway, testosterone is converted to the C18 estrogen estradiol in the ovaries.
[click to see the ontology report for related GO term - , associated KEGG map - and related entry at Reactome - ] The steroid hormone biosynthetic pathway is part of the and the .� Click the name of the suite to view the related pathways.
Either progesterone or 17OH-pregnenolone can lead to the formation of the C21 glucocorticoid cortisol in the cortisol biosynthetic pathway in zona fasciculata.
In the adrenal zona glomerulosa, progesterone is converted to the C21 mineralocorticoid aldosterone via a number of steps in the aldosterone biosynthetic pathway.
Steroid biosynthesis pathway. CYP11family is involved in numerous steroid biosynthesis pathways. Bluecolor corresponds to downregulated expression; red colorcorresponds to mutation. CYP, cytochrome P450; SULT2B1,sulfotransferase family cytosolic 2B member 1; STS, sequence taggedsite; HDS3β, hydroxysteroid dehydrogenase 3β.
From this point, the pathway diverges into the individual branches that lead to the synthesis of particular types of steroids at specific adrenal and gonadal locations.
Cytochromes P450 (CYPs) belong to a superfamily ofproteins that contain a heme cofactor. They are primarily locatedin the inner membrane of mitochondria or the endoplasmic reticulumof cells (). CYPs, as the oxidaseenzymes in electron transfer chains, catalyze a number of enzymaticreactions involving small molecules. The CYPs are classified asendogenous CYPs or xenobiotic CYPs. The endogenous CYPs areinvolved with the biosynthesis or catabolism of steroids, sterols,retinoids, prostaglandins and fatty acids, while the xenobioticCYPs function to defend against environmental toxins andcarcinogens (). The human CYP family1–4 includes the major enzymes involved in drug metabolism,accounting for ~75% of the total CYPs ().
In the human body, the CYP11 gene family, includingCYP11A1, CYP11B1 and CYP11B2, is one of the families of CYP genesinvolved in steroid biosynthesis ().Previously, almost no research has been conducted with regards tothe CYP11 family and cancer; therefore, the present study aimed toinvestigate the associations between them. The results of thepresent study may be important for expanding the global view ofcancer research.
AB - Steroid hormones are ancient signaling molecules found in vertebrates and insects alike. Both taxa show intriguing parallels with respect to how steroids function and how their synthesis is regulated. As such, insects are excellent models for studying universal aspects of steroid physiology. Here, we present a comprehensive genomic and genetic analysis of the principal steroid hormone-producing organs in two popular insect models, Drosophila and Bombyx. We identified 173 genes with previously unknown specific expression in steroid-producing cells, 15 of which had critical roles in development. The insect neuropeptide PTTH and its vertebrate counterpart ACTH both regulate steroid production, but molecular targets of these pathways remain poorly characterized. Identification of PTTH-dependent gene sets identified the nuclear receptor HR4 as a highly conserved target in both Drosophila and Bombyx. We consider this study to be a critical step toward understanding how steroid hormone production and release are regulated in all animal models.
Pregnenolone is a type of endogenous steroid, and isthe forerunner of several steroids, including glucocorticoids,mineralocorticoids, progestogens, estrogens and androgens (). Furthermore, pregnenolone is abiologically active neurosteroid (). Pregnenolone is synthesized fromcholesterol, a transversion that requires hydroxylation at the C20and C22 positions of the side-chain and is performed by the enzymeCYP11A1, which is located in the mitochondria and is controlled byanterior pituitary tropic hormones. Cortisol (a glucocorticoidsteroid hormone) is composed by the zona fasciculata of the adrenalcortex. During stress or hypoglycemia, cortisol will be released tosuppress the immune system, to increase blood glucose, to decreasebone formation and to support the metabolism of carbohydrates, fatand protein (,). Aldosterone (a mineralocorticoidsteroid hormone) is formed by the zona glomerulosa of the adrenalcortex, and is important for blood pressure regulation (). Blood pressure is managed by processesthat occur in the distal convoluted tubules and collecting ducts ofthe nephron, which encourage the reabsorption of ions and water,the secretion of potassium, the conservation of sodium, and theincrease in water retention, blood volume and blood pressure().
AB - Epithelial ovarian tumors are responsive to steroid hormone stimulation and the ovarian stroma may have a direct role in this process. We evaluated immunohistochemical markers of sex-steroid differentiation and steroidogenesis (calretinin, inhibin, steroidogenic factor 1), steroid enzymes involved in hormone biosynthesis (CYP17, CYP19, HSD17β1, AKR1C3), and hormone receptors (estrogen receptor, progesterone receptor, and androgen receptor) in 101 epithelial ovarian tumors and in normal structures implicated in ovarian carcinogenesis (ovarian surface epithelium and cortical inclusion cysts) in an attempt to elucidate this process. We hypothesized that ovarian stroma immediately adjacent to tumors express markers of sex-steroid differentiation and steroidogenesis and steroid enzymes whereas the epithelium contains corresponding hormone receptors. As the findings in seromucinous, endometrioid, and clear cell neoplasms, tumors closely associated with endometriosis, were very similar, these were combined into a group designated ‘endometriosis-related tumors.’ Significantly increased expression of markers of sex-steroid differentiation and steroidogenesis was found in stroma immediately adjacent to endometriosis-related tumors (P=0.003) and mucinous tumors (primary and metastatic mucinous tumors were combined because of similar findings) (P
Decreased expression and mutations of the CYP11family may influence the biosynthesis of steroid hormones. Inrecent years, the majority of studies of steroid hormones have beenperformed in breast cancer patients (–).However, studies have investigated the role of steroid hormones inprostate (), lung (), endometrial (), colon () and liver cancer (). Steroid hormones have been demonstratedto activate focal adhesion kinase, which regulates early actinreorganization in colon cancer cells (). Steroid hormones were not previouslyconsidered to be involved with lung function (); however, numerous studies have reportedthat steroid hormones are important in normal lung development andfunction () and in thepathogenesis of pulmonary diseases, including lung cancer (–). Astudy of prostate cancer validated the hypothesis that thebiosynthesis of steroid hormones downstream of CYPs contributes tothe progression of castration-resistant prostate cancer (). Steroid hormones may also be utilizedfor the treatment of endometrial cancer. For example, progestintherapy has been demonstrated as a viable treatment option for type1 endometrial cancer (). Thesestudies support the results of the present study, which indicatedthat steroid hormones are extremely important in numerous cancertypes. In conclusion, the CYP11 family, which may affect steroidbiosynthesis, is commonly involved in various types of cancer. Thepresent study provides novel ideas that indicate that, with thedevelopment of technology, the CYP11 family could used as biomarkeror drug target in the future research of cancers. Additional dataand experiments will help to determine whether the genes of CYP11family may be used as biomarkers in the diagnosis of various typesof cancer. The method of computer-aided drug design may be used tosimulate the interaction between the CYP11 family and chemicalmolecules, which will verify whether the CYP11 family could becomedrug targets.