Enzymatic Metabolism of Ergosterol by Cytochrome P450scc to Biologically Active 17α,24-Dihydroxyergosterol

Slominski, Andrzej; Semak, Igor; Zjawiony, Jordan K.; Wortsman, Jacobo; Gandy, Michael; Li, Jinghu; Zbytek, Blazej; Li, Wei; Tuckey, Robert C.

doi:10.1016/j.chembiol.2005.06.010

Cited by 67 publications

(80 citation statements)

References 37 publications

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“…Most recently, it has been uncovered that the classical enzyme of steroidogenesis cytochrome P450scc can also cleave the side chain of 7-DHC to produce 7-dehydropregnenolone (7-DHP) identifying a novel metabolic pathway producing 5,7 diene hydroxysteroids that after UVB exposure could generate secosteroidal vitamin D-like (VitDL) products [137,138]. Moreover, vitamin D3, ergosterol (provitamin D2) and vitamin D2 are additionally metabolized by the same P450scc producing hydroxyderivatives [42,139,140], some of which induce differentiation and inhibit proliferation of skin cells [139,141]. Thus, new family of vitamin D derivatives was identified that could be tested for its potential antimelanoma activity.…”

Section: Glucocorticoids Receptorsmentioning

confidence: 99%

Melanocyte Receptors: Clinical Implications and Therapeutic Relevance

Carlson

Linette

Aplin

et al. 2007

Dermatologic Clinics

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Melanocytes are an intraepidermal population of dendritic cells responsible for the production of melanin, a pigment that varies from yellow to brown to black pigment that after transfer to neighboring keratinocytes acts both as an endogenous screen and a buffering system against harmful ultraviolet (UV) wavelengths in sunlight [1]. Skin pigmentation has both individual and societal implications. The cosmetic desire for increased pigmentation (tanning) has resulted in many deleterious alterations including hastened skin ageing with wrinkles and poikiloderma and an increase in lentigines, melanocytic nevi, and melanoma. Focal or widespread loss of normal pigmentation not only renders individuals extraordinarily vulnerable to the harmful effects of sunlight (eg, increased risk of skin cancer in albinism), but it can also result in severe emotional stress and, in some societies, ostracism and discrimination (eg, vitiligo).Melanocytes are derived from the neural crest and are located along the basal layer of the epidermis and within the hair follicle, predominately the basal layer of the hair bulb matrix [1,2]. By the 50th day of intrauterine life, melanocytes can be detected in the epidermis; their migration to the epidermis and survival is dependent on receptor tyrosine kinase (RTK) c-Kit and its ligand stem cell factor (SCF) within the epidermis [3,4]. Mutations of the c-Kit gene lead to patches of hypopigmentation caused by lack of melanocyte migration, termed piebaldism [5]. Another important signaling molecule in melanocyte migration and development is Wnt5a, which signals via the Frizzled-5 receptor [6]. Overexpression of Wnt5a/ Frizzled is found in melanomas and associated with increased cell motility and invasiveness [7,8].Skin keratinocytes obtain melanin pigment from melanocytes, and keratinocytes provide the necessary microenvironment for melanocyte survival, proliferation, differentiation, and migration via production of ligands that interact with melanocyte receptors [1,[9][10][11] NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript epidermal melanin unit denotes the symbiotic relationship between one melanocyte transporting melanin via its dendritic processes to approximately 36 keratinocytes [10]. Melanocytes are located on the basement membrane among basal keratinocytes at ratio of 1 melanocyte per 5 basal keratinocytes in hematoxylin and eosin-stained histologic sections. This balance is maintained through regulated induction of melanocyte division. During childhood as the skin surface expands, throughout adulthood to maintain melanocyte numbers, and in response to exposure to sunlight or skin wounding, melanocytes are stimulated to proliferate at a low rate. Melanocyte proliferation entails uncoupling from keratinocytes, loss of their dendrites, cell division, migration along the basement membrane, then recoupling with keratinocytes to form the epidermal melanin unit. Keratinocytes regulate melanocyte growth and expression of melanocyte cell surface receptors via cell adhes...

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Section: Glucocorticoids Receptorsmentioning

confidence: 99%

Melanocyte Receptors: Clinical Implications and Therapeutic Relevance

Carlson

Linette

Aplin

et al. 2007

Dermatologic Clinics

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“…Thus, when topically applied, ergosterol may serve as a substrate for P450scc with potential implications in therapy of skin hyperproliferative or inflammatory disorders. In fact previous experiments indicate that dihydroxyergosterol metabolites of bovine P450scc can inhibit proliferation of immortalized human epidermal keratinocytes (Slominski et al, 2005b).…”

Section: Introductionmentioning

confidence: 99%

“…We have previously reported that bovine P450scc can hydroxylate ergosterol producing 17␣,24-dihydroxyergosterol as the major product with no evidence for cleavage of the side chain (Slominski et al, 2005b). Having the same side chain as ergosterol, vitamin D 2 is metabolized by bovine P450scc to 20-hydroxyvitamin D 2 , 17,20-dihydroxyvitamin D 2 , and 17,20,24-trihydroxyvitamin D 2 (Nguyen et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…20-Hydroxyvitamin D 2 inhibits proliferation and stimulates differentiation of keratinocytes, melanocytes, and leukemia cells in a similar fashion to 1␣,25-dihydroxyvitamin D 3 , but unlike this hormone, it lacks calcemic activity in rats and, therefore, has therapeutic potential (Slominski et al, 2011). Opening of the B-ring of the steroid is not required for biological activity because the 17␣,24-dihydroxyergosterol produced by bovine P450scc can inhibit the proliferation of both human keratinocytes and melanocytes (Slominski et al, 2005b). Steroids derived from 7-dehydrocholesterol (the vitamin D 3 precursor), observed in Smith-Lemli-Opitz syndrome (Shackleton et al, 2002), have also been shown to exhibit biological activity on skin cells without B-ring opening .…”

Section: Introductionmentioning

confidence: 99%

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Human Cytochrome P450scc (CYP11A1) Catalyzes Epoxide Formation with Ergosterol

Tuckey¹,

Nguyen²,

Chen³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Cytochrome P450scc (P450scc) catalyzes the cleavage of the side chain of both cholesterol and the vitamin D 3 precursor, 7-dehydrocholesterol. The aim of this study was to test the ability of human P450scc to metabolize ergosterol, the vitamin D 2 precursor, and define the structure of the major products. P450scc incorporated into the bilayer of phospholipid vesicles converted ergosterol to two major and four minor products with a k cat of 53 mol ⅐ min

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“…The reaction involves removal of the side chain of cholesterol via production of enzyme-bound intermediates, 22R-hydroxycholesterol and 20α,22R-dihydroxycholesterol (Hume et al, 1984;Lambeth et al, 1982;Tuckey, 1990Tuckey, , 2005. Cytochrome P450scc can also metabolize vitamin D3 (D3) and vitamin D2 (D2), as well as their precursors 7-dehydrocholesterol and ergosterol (Guryev et al, 2003;Slominski et al, 2004Slominski et al, , 2005aSlominski et al, ,b, 2006Tuckey et al, 2008). Our most recent study shows that P450scc can hydroxylate D3 at carbons 17, 20 and 23 (Tuckey et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Kinetics of vitamin D3 metabolism by cytochrome P450scc (CYP11A1) in phospholipid vesicles and cyclodextrin

Tuckey

Nguyen

Slominski

2008

The International Journal of Biochemistry & Cell Biology

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Vitamin D3 can be hydroxylated sequentially by cytochrome P450scc (CYP11A1) producing 20-hydroxyvitamin D3, 20,23-dihydroxyvitamin D3 and 17,20,23-trihydroxyvitamin D3. The aim of this study was to characterize the ability of vitamin D3 to associate with phospholipid vesicles and to determine the kinetics of metabolism of vitamin D3 by P450scc in vesicles and in 2-hydroxypropyl-β-cyclodextrin (cyclodextrin). Gel filtration of phospholipid vesicles showed that the vitamin D3 remained quantitatively associated with the phospholipid membrane. Vitamin D3 exchanged between vesicles at a rate 3.8-fold higher than for cholesterol exchange and was stimulated by N-62 StAR protein. The K m of P450scc for vitamin D3 in vesicles was 3.3 mol vitamin D3/mol phospholipid and the rate of conversion of vitamin D3 to 20-hydroxyvitamin D3 was first order with respect to the vitamin D3 concentration for the range of concentrations of vitamin D3 that could be incorporated into the vesicle membrane. 20-Hydroxyvitamin D3 was further hydroxylated by P450scc in vesicles, producing primarily 20,23-dihydroxyvitamin D3, with K m and k cat values 22-and 6-fold lower than those for vitamin D3, respectively. 20,23-Dihydroxyvitamin D3 was converted to 17,20,23-trihydroxyvitamin D3 with even lower K m and k cat values. Vitamin D3 and cholesterol were metabolized with comparable efficiencies in cyclodextrin, but the K m for both showed a strong dependence on the cyclodextrin concentration, decreasing with decreasing cyclodextrin. This study shows that vitamin D3 quantitatively associates with phospholipid vesicles, can exchange between membranes, and can be hydroxylated by membrane-associated P450scc but with lower efficiency than for cholesterol hydroxylation. The k cat values for metabolism of vitamin D3 in vesicles and 0.45% cyclodextrin are similar, but the ability to solubilize vitamin D3 at a concentration higher than its K m makes the cyclodextrin system more efficient for producing the hydroxyvitamin D3 metabolites for further characterization.

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Enzymatic Metabolism of Ergosterol by Cytochrome P450scc to Biologically Active 17α,24-Dihydroxyergosterol

Cited by 67 publications

References 37 publications

Melanocyte Receptors: Clinical Implications and Therapeutic Relevance

Melanocyte Receptors: Clinical Implications and Therapeutic Relevance

Human Cytochrome P450scc (CYP11A1) Catalyzes Epoxide Formation with Ergosterol

Kinetics of vitamin D3 metabolism by cytochrome P450scc (CYP11A1) in phospholipid vesicles and cyclodextrin

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