CYP17- and CYP11B-dependent steroid hydroxylases as drug development targets

Hakki, Tarek; Bernhardt, Rita

doi:10.1016/j.pharmthera.2005.07.006

Cited by 85 publications

(54 citation statements)

References 142 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The A2 allele of the CYP17 gene is responsible for increased estrogen levels, and, more recently, the steroid hydroxylases themselves have been found to be promising new targets for drug development. Instead of the use of anti-hormones to inhibit the action of steroid hormones at the level of steroid hormone receptors CYPs may be used to help in the development of new inhibitors of hydroxylase enzymes (Hakki and Bernhardth 2006).…”

Section: Discussionmentioning

confidence: 99%

CYP17 gene polymorphism and its association with high-risk north Indian breast cancer patients

Chakraborty

Murthy²,

Chintamani

et al. 2007

J Hum Genet

View full text Add to dashboard Cite

A single T > C change at the 5¢ promoter region of the CYP17 gene is reported to be associated with increased risk of breast cancer. This study evaluates the influence of genetic polymorphism of CYP17 on breast cancer susceptibility. Two hundred and fortytwo patients with histopathologically confirmed breast cancer and 212 age-matched controls were included in the present study. Information relating to age at onset of the disease, family history and estrogen receptor status was elicited. Investigation for CYP17 polymorphism was carried out in 106 early onset, 80 late onset and 56 familial cases. The frequencies of two CYP17 alleles were also analyzed in 116 (47.9%) cases with known estrogen receptor (ER) status confirmed immunohistochemically. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect the polymorphism, and the genotypes identified were assigned as homozygous wild type (A1A1), heterozygous variant (A1A2), and homozygous variant (A2A2). Associations between the various genotypes in patients and controls were investigated with Fisher's exact test. All the tests were two tailed. The results showed that the frequency of heterozygous and homozygous CYP17 genotype was higher in early onset breast cancer patients (94.3%) than in controls (80.3%), and the difference was significant (P = 0.001). A highly statistically significant increased risk in carriers of homozygous A2 allele was found in young patients (P £ 0.001) in comparison with patients having late onset condition (P = 0.260). However, no significant association between the genotype and breast cancer risk was observed among women with strong family history. Further, data had showed that patients (80.6%) with at least one A2 allele tended to exhibit ER-independent cell proliferation, although statistical significance could not be established (P = 0.160). The present findings suggest that CYP17 A2 allele gene polymorphism might play a significant role in breast cancer development in young Indian women.

show abstract

Section: Discussionmentioning

confidence: 99%

CYP17 gene polymorphism and its association with high-risk north Indian breast cancer patients

Chakraborty

Murthy²,

Chintamani

et al. 2007

J Hum Genet

View full text Add to dashboard Cite

show abstract

“…Central to these processes, and deterministic in the paths to the major classes of androgens, estrogens and mineral corticoids is the regio-and stereo-specific action by a variety of cytochrome P450 (CYP) proteins. For instance, formation of the androgens requires attack at the 17-carbon to form a 17-keto group at the apex of the D ring while estrogens are formed by attack at the 19-carbon which leads to aromatization of the A-ring (see refs [2,3] for general review). In humans, this latter reaction is catalyzed by the microsomal CYP19, and has emerged as an important pharmaceutical target for the treatment of estrogen-dependent breast cancers [4] as well as non-small cell lung carcinomas [5] CYP19 is thought to catalyze three distinct reactions [6,7].…”

Section: Introductionmentioning

confidence: 99%

The ferrous-oxy complex of human aromatase

Grinkova

Denisov

Waterman

et al. 2008

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

In this communication, we document the self-assembly of heterologously expressed truncated human aromatase (CYP19) into nanometer scale phospholipids bilayers (Nanodiscs). The resulting P450 CYP19 preparation is stable, and can tightly associate the substrate androstenedione to form a nearly complete high-spin ferric protein. Ferrous CYP19 in Nanodiscs was mixed anaerobically in a rapidscan stopped-flow with atmospheric dioxygen and the formation of the ferrous-oxy complex observed. First order decay of the oxy-complex to release superoxide and regenerate the ferric enzyme was monitored kinetically. Surprisingly, the ferrous-oxy complex of aromatase is more stable that of hepatic CYP3A4, opening the path to precisely determine the biochemical and biophysical properties of the reaction cycle intermediates in this important human drug target.

show abstract

“…For example, in humans, CYP17A1 and CYP19A1 catalyze steps in the production of androgens and estrogens (9). CYP26B1 metabolizes retinoic acid and is involved in the fate of germ cells in the testes of mice (10).…”

mentioning

confidence: 99%

Characterization of Drosophila melanogaster cytochrome P450 genes

Chung

Sztal

Pasricha

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

259

235

View full text Add to dashboard Cite

Cytochrome P450s form a large and diverse family of hemecontaining proteins capable of carrying out many different enzymatic reactions. In both mammals and plants, some P450s are known to carry out reactions essential for processes such as hormone synthesis, while other P450s are involved in the detoxification of environmental compounds. In general, functions of insect P450s are less well understood. We characterized Drosophila melanogaster P450 expression patterns in embryos and 2 stages of third instar larvae. We identified numerous P450s expressed in the fat body, Malpighian (renal) tubules, and in distinct regions of the midgut, consistent with hypothesized roles in detoxification processes, and other P450s expressed in organs such as the gonads, corpora allata, oenocytes, hindgut, and brain. Combining expression pattern data with an RNA interference lethality screen of individual P450s, we identify candidate P450s essential for developmental processes and distinguish them from P450s with potential functions in detoxification.detoxification genes ͉ in situ hybridization ͉ insecticide resistance ͉ multigene family ͉ RNAi

show abstract

CYP17- and CYP11B-dependent steroid hydroxylases as drug development targets

Cited by 85 publications

References 142 publications

CYP17 gene polymorphism and its association with high-risk north Indian breast cancer patients

CYP17 gene polymorphism and its association with high-risk north Indian breast cancer patients

The ferrous-oxy complex of human aromatase

Characterization of Drosophila melanogaster cytochrome P450 genes

Contact Info

Product

Resources

About