Abstract
BackgroundCytochrome P450scc metabolizes vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,23(OH)2D3, as well as 1-hydroxyvitamin D3 to 1α,20-dihydroxyvitamin D3 (1,20(OH)2D3). It also cleaves the side chain of 7-dehydrocholesterol producing 7-dehydropregnenolone (7DHP), which can be transformed to 20(OH)7DHP. UVB induces transformation of the steroidal 5,7-dienes to pregnacalciferol (pD) and a lumisterol-like compounds (pL).Methods and FindingsTo define the biological significance of these P450scc-initiated pathways, we tested the effects of their 5,7-diene precursors and secosteroidal products on leukemia cell differentiation and proliferation in comparison to 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). These secosteroids inhibited proliferation and induced erythroid differentiation of K562 human chronic myeloid and MEL mouse leukemia cells with 20(OH)D3 and 20,23(OH)2D3 being either equipotent or slightly less potent than 1,25(OH)2D3, while 1,20(OH)2D3, pD and pL compounds were slightly or moderately less potent. The compounds also inhibited proliferation and induced monocytic differentiation of HL-60 promyelocytic and U937 promonocytic human leukemia cells. Among them 1,25(OH)2D3 was the most potent, 20(OH)D3, 20,23(OH)2D3 and 1,20(OH)2D3 were less active, and pD and pL compounds were the least potent. Since it had been previously proven that secosteroids without the side chain (pD) have no effect on systemic calcium levels we performed additional testing in rats and found that 20(OH)D3 had no calcemic activity at concentration as high as 1 µg/kg, whereas, 1,20(OH)2D3 was slightly to moderately calcemic and 1,25(OH)2D3 had strong calcemic activity.ConclusionsWe identified novel secosteroids that are excellent candidates for anti-leukemia therapy with 20(OH)D3 deserving special attention because of its relatively high potency and lack of calcemic activity.
Highlights
In vivo, vitamin D3 (D3) is generated in the epidermis through photochemical transformation of 7-dehydrocholesterol (7DHC) after absorption of ultraviolet radiation B (UVB; wavelength 280– 320 nm) energy [1,2,3,4]
Vitamin D3 is hydroxylated by P450scc to 20(OH)D3 and 20,23(OH)2D3 [22,23], while 1,20(OH)2D3 is generated through hydroxylation of 1(OH)D3 by P450scc [28] or by the action of 1a-hydroxylase on 20(OH)D3 [33]. 20(OH)D3 can derive from UVB induced photolytic transformation of 20(OH)7DHC that is produced by hydroxylation of 7DHC by P450scc [29]. 20(OH)7DHC is further transformed to 7DHP by P450scc [29,30] after absorption of UVB photons forms pD or pL depending on the UV energy [32]. 7DHP is potentially reduced by 20-hydroxysteroid dehydrogenase to 20(OH)7DHP [30] which undergoes UVB induced transformation to 20(OH)pD [31]
Since P450scc hydroxylates the side chain of D3 and 1(OH)D3 at C20, we tested the calcemic effects of the resulting products in rats at a doses 0.1 mg/kg–3 mg/kg of body weight (Fig. 1). 20(OH)D3 at dose as high as 3.0 mg/kg had no calcemic activity, whereas 1,25(OH)2D3 at the same dose had the expected strong calcemic effect raising calcium to 16.061.2 mg/dL
Summary
Vitamin D3 (D3) is generated in the epidermis through photochemical transformation of 7-dehydrocholesterol (7DHC) after absorption of ultraviolet radiation B (UVB; wavelength 280– 320 nm) energy [1,2,3,4]. The active form of vitamin D3, 1,25(OH)2D3, is generated systemically through sequential 25and 1a– hydroxylation in the liver and kidney, respectively [4,5]. It is produced locally in different organs including skin [5,6]. Cytochrome P450scc metabolizes vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,23(OH)2D3, as well as 1-hydroxyvitamin D3 to 1a,20-dihydroxyvitamin D3 (1,20(OH)2D3). It cleaves the side chain of 7-dehydrocholesterol producing 7-dehydropregnenolone (7DHP), which can be transformed to 20(OH)7DHP. UVB induces transformation of the steroidal 5,7-dienes to pregnacalciferol (pD) and a lumisterol-like compounds (pL)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
