Disease relevance of CYP17A1

• In conclusion, our results suggest that several SNPs along the androgen pathway, especially in CYP19A1 and CYP17A1, may influence prostate cancer development and progression [1].
• The position -34T/C variant in CYP17A1 appears to be associated with reduced risk of endometrial cancer, with those homozygous for the variant allele having about half the risk of those homozygous for the wild type [2].
• Diffuse large-cell lymphoma risk was increased for those with CYP17A1 polymorphisms including CYP17A1 -34CC (OR, 2.0; 95% CI, 1.1-3.5) [3].
• CYP17A1-34T>C and CYP17A1 IVS2 105A>C polymorphisms were analyzed in a non-Hodgkin lymphoma (NHL) population-based case-control study [4].
• A positive association exists between birth weight and the homozygous CYP17A1 A2 genotype (P<0.01) [5].
• This study showed that a polymorphism in CYP17 (c.-34T-->C) modifies age at onset of Lynch syndrome [6].

High impact information on CYP17A1

• Computer-graphic modelling of P450c17 suggests that both mutations lie in or near the redox-partner binding site, on the opposite side of the haem from the substrate-binding pocket [7].
• P450c17 alpha, which is involved in androgen biosynthesis, has both 17 alpha-hydroxylase and 17,20-lyase activities [8].
• Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome [8].
• BACKGROUND: Insulin resistance and increased ovarian cytochrome P450c17 alpha activity are both features of the polycystic ovary syndrome [8].
• CONCLUSIONS: In obese women with the polycystic ovary syndrome, decreasing serum insulin concentrations with metformin reduces ovarian cytochrome P450c17 alpha activity and ameliorates hyperandrogenism [8].

Chemical compound and disease context of CYP17A1

• Cytochrome P450 17A1 (CYP17A1), a key enzyme in estrogen biosynthesis, has been associated with increased cancer risk and may affect lymphoma susceptibility [3].
• Mutant CYP 17 alleles are associated with serum and plasma levels of steroid hormones, use of hormone replacement therapy, and endometrial, prostate, and breast cancer [9].
• 1. Aminopyrine N-demethylase activity was determined for 11 forms of human hepatic cytochrome P450s (P450s) expressed in yeast Saccharomyces cerevisiae and for human steroidogenic CYP17 expressed in Escherichia coli [10].
• Congenital adrenal hyperplasia results from a deficiency in any of the five enzymes necessary to synthesize cortisol from cholesterol: cholesterol desmolase (P450scc), 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), 17-hydroxylase (P450c17), 21-hydroxylase (P450c21) and 11-hydroxylase (P450c11) [11].
• A chimeric construct of mouse CYP1B1 in which the 20 NH2-terminal amino acids have been replaced by eight residues from human CYP17 has been expressed in Escherichia coli [12].

Biological context of CYP17A1

• The -34T --> C polymorphism of CYP17A1 was associated with BMD in postmenopausal women, with the CC genotype being related to increased BMD [13].
• Results indicate the need to study other variants and haplotypes in these genes, particularly CYP17A1 and CYP19A1, as well as variants in other genes involved in hormone biosynthesis and metabolism pathways [2].
• Association of polymorphisms in CYP17A1, MTP, and VLDLR with bone mineral density in community-dwelling Japanese women and men [13].
• We investigated the association between 2 common polymorphisms in 1) the promoter region (T-->C substitution) of CYP 17, and 2) exon 3 (G-->A) of CYP 19, bone mineral density (BMD) and serum androgen/estradiol, in a case-control study of 252 postmenopausal women aged 64.5 +/- 9.2 yr (mean +/- SD) [14].
• In this study we examined the role of changes in phosphorylation state on the expression and transcriptional activity of the human CYP17 gene (hCYP17) [15].

Anatomical context of CYP17A1

• Aldosterone synthase (CYP11B2) messenger ribonucleic acid was detected in the aorta and fetal heart, but not in any region of the adult heart, and 17alpha-hydroxylase (CYP17) was not detected in any cardiac sample [16].
• Adrenocorticotropin/cyclic adenosine 3',5'-monophosphate-mediated transcription of the human CYP17 gene in the adrenal cortex is dependent on phosphatase activity [15].
• Thus, specific set of genetic polymorphisms (carrying of CYP17 A1 allele and combination of longest A6 or A7 CYP19 alleles) may predispose to the induction of higher rate of local estrogen biosynthesis in malignant endometrium, that in its turn may support growth of the latter [17].
• The male baby born of this pregnancy had normal genitalia but showed a urinary steroid profile indicating partial deficiencies of P450c17 and P450c21 [18].
• Since high 17,20-lyase activity is required for the production of androgens in the testis, we wanted to determine the importance of this second cDNA in the modulation of P450c17 17,20-lyase activity and hence, its role in the formation of active androgens [19].

Associations of CYP17A1 with chemical compounds

• RESULTS: In the PORD patients, pregnanediol, pregnanetriolone, and pregnanetriol were obviously elevated, and the urine steroid ratios reflecting CYP17A1 and CYP21A2 activities were decreased throughout the examined ages [20].
• Blood cholesterol was grossly normal, and endocrine studies revealed defective CYP17A1 and CYP21A2 activities [21].
• Late-stage ER alpha-null follicles exhibited markedly increased expression of the thecal cell enzyme CYP17A1 and secreted much greater amounts of its end product, androstenedione [22].
• The results suggest that the estrogen-metabolizing CYP17 genotype influences age at menarche in healthy postmenopausal Japanese women [23].
• Few associations were found for CYP17 and CYP1B1 or with serum androgen concentrations [24].

Physical interactions of CYP17A1

• Transcription of the cytochrome P450 17 (CYP17) gene is regulated by cAMP-dependent binding of steroidogenic factor-1 (SF-1) to its promoter in the adrenal cortex [25].
• Lysine mutagenesis identifies cationic charges of human CYP17 that interact with cytochrome b5 to promote male sex-hormone biosynthesis [26].
• Thus, CRH is coupled to the phospholipase C-inositol phosphate second messenger system and preferentially induces the expression of P450c17 and DHEAS, suggesting a unique role of CRH regulating human fetal adrenal function via PKC [27].

Enzymatic interactions of CYP17A1

• 3. Human steroidogenic CYP17 also catalysed aminopyrine N-demethylation and the activity was comparable with that for CYP3A4 which is a dominant P450 in human liver [10].
• Like the pig CYP17, the human CYP17 also catalysed the cytochrome b5-dependent direct cleavage of pregnenolone into the delta 5,16-steroid, but unlike it the human enzyme did not cleave progesterone at all [28].

Regulatory relationships of CYP17A1

• Cyclic adenosine 5'-monophosphate-dependent sphingosine-1-phosphate biosynthesis induces human CYP17 gene transcription by activating cleavage of sterol regulatory element binding protein 1 [29].
• DKK3 decreased cyclic AMP-stimulated CYP17 [30].
• We also evaluated associations between CYP17 genotype and plasma steroid hormones among controls and the potential interaction between CYP17 and SRD5A2 V89L polymorphisms in relationship with prostate cancer risk and circulating steroid hormone levels [31].
• The metabolism of bisphenol A (BPA) was determined for 11 forms of human hepatic cytochromes P450 (CYPs) expressed in the yeast Saccharomyces cerevisiae and for human steroidogenic CYP17 expressed in Escherichia coli [32].
• These data provide essential evidence in support of a functional role for cytochrome b5 in the regional control of 17alpha-hydroxylase and 17,20-lyase activities of P450c17 and thereby adrenal C19 steroid secretion by the primate adrenal gland [33].

Other interactions of CYP17A1

• CYP17 (P = 0.05) and TP53 (P = 0.06) polymorphisms showed marginally significant associations in unstratified analyses [34].
• CAMP-dependent protein kinase enhances CYP17 transcription via MKP-1 activation in H295R human adrenocortical cells [35].
• We found no significant associations between breast density and the variant alleles for CYP1A1, CYP1B1 and CYP17 [36].
• Transcriptional activation of human CYP17 in H295R adrenocortical cells depends on complex formation among p54(nrb)/NonO, protein-associated splicing factor, and SF-1, a complex that also participates in repression of transcription [37].
• In summary, our studies demonstrate a role for sphingolipid metabolism and SREBP1 in ACTH-dependent CYP17 regulation and steroidogenesis [29].

Analytical, diagnostic and therapeutic context of CYP17A1

• Chromatin immunoprecipitation assays revealed that Bt2cAMP and S1P increased acetylation of histone H3 and promoted binding of SREBP1 to the -520/-331 region of the CYP17 promoter [29].
• RESULT(S): The model incorporates the number of full term pregnancies, the body mass index (BMI), a history of breast surgery, and the presence of CYP17 and CYP1B1-4 polymorphisms as well as the BMI to predict age at natural menopause and the risk for undergoing premenopausal hysterectomy [38].
• We therefore isolated type 2 cyt-b5 from human testis by RT-PCR and analyzed, by transient transfection in transformed human embryonic kidney cells (HEK-293) of various amounts of vectors expressing cyt-b5, P450-reductase and P450c17, its ability to modulate the 17,20-lyase activity of human P450c17 [19].
• Association with CYP17 genotype was modified by body mass index (BMI) [39].
• Human C-terminal FLAG-tagged P450c17 chromosomal DNA was subjected to site-directed mutagenesis [40].

References