Structures and biological activities of vitamin D metabolites and their analogs

Ikekawa, Nobuo

doi:10.1002/med.2610070304

Cited by 75 publications

(20 citation statements)

References 208 publications

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“…The findings need to be verified in a prospective study, as these issues have major implications for supplementation strategies. If protective effects of 1,25-D are shown, chemoprevention and/or chemotherapy using vitamin D analogues-synthetic compounds with effects on cellular growth and differentiation with minimized effect on calcium metabolism [46][47][48] -would be an important area of investigation. from the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, and by the Department of Defense DAMD 17-94-J-4344.…”

Section: Discussionmentioning

confidence: 99%

Association between low levels of 1,25-dihydroxyvitamin D and breast cancer risk

Janowsky

Lester

Weinberg

et al. 1999

Public Health Nutr.

135

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Objective: To determine if blood levels of 25-hydroxyvitamin D (25-D) or its active metabolite, 1,25-dihydroxyvitamin D (1,25-D), are lower in women at the time of first diagnosis of breast cancer than in comparable women without breast cancer. Design: This was a clinic-based case-control study with controls frequency-matched to cases on race, age, clinic and month of blood drawing. Setting: University-based breast referral clinics. Subjects: One hundred and fifty-six women with histologically documented adenocarcinoma of the breast and 184 breast clinic controls. Results: There were significant mean differences in 1,25-D levels (pmol ml) between breast cancer cases and controls; white cases had lower 1,25-D levels than white controls (mean difference Ϯ SE: −11.08 Ϯ 0.76), and black cases had higher 1,25-D levels than black controls (mean difference Ϯ SE: 4.54 Ϯ 2.14), although the number of black women in the study was small. After adjustment for age, assay batch, month of blood draw, clinic and sample storage time, the odds ratio (95% confidence interval, CI) for lowest relative to highest quartile was 5.2 (95% CI 2.1, 12.8) for white cases and controls. The association in white women was stronger in women above the median age of 54 than in younger women, 4.7 (95% CI 2.1, 10.2) vs. 1.5 (95% CI 0.7, 3.0). There were no case-control differences in 25-D levels in either group. Conclusions: These data are consistent with a protective effect of 1,25-D for breast cancer in white women.

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Section: Discussionmentioning

confidence: 99%

Association between low levels of 1,25-dihydroxyvitamin D and breast cancer risk

Janowsky

Lester

Weinberg

et al. 1999

Public Health Nutr.

135

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“…The therapeutic potentials of this pleiotropic secosteroid, especially its low calcemic analogs (Ikekawa and Ishizuka 1992), must be high and multiple. This is indicated from the listing of the autoradiographically identified genomic target tissues, the related immunohistochemical information and measurements of secretory products, as well as experimental evidence on cell proliferation and differentiation published in the literature.…”

Section: Therapeutic Potentialsmentioning

confidence: 99%

Vitamin D sites and mechanisms of action: A histochemical perspective. Reflections on the utility of autoradiography and cytopharmacology for drug targeting

Stumpf¹

1995

Histochem Cell Biol

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Knowledge about sites and mechanisms of action of vitamin D and its analogs has been greatly advanced by histochemical approaches. High resolution and high sensitivity, combined with the integrative potential of relatively intact histochemical tissue preparations, contributed information that is difficult or impossible to obtain otherwise. In in vivo distribution studies with conventional biochemical assays, target cell populations associated with non-target tissues frequently remain unrecognized without the resolution achieved by cellular autoradiography. Autoradiography, alone or combined with immunohistochemistry when applied to in vivo drug targeting and target characterization, has provided information on cellular-subcellular receptor distribution in over 50 tissues. These discoveries, importantly, contribute to a new understanding of the biological role of vitamin D and challenge the concept of "the calcium homeostatic steroid hormone" as being too narrow. While some of the outstanding effects of vitamin D deficiency and toxicity relate to calcium homeostasis, the vast majority of the target tissues appear not to be primarily related to calcium metabolism, but rather to the activation and regulation of exo- and endocrine secretory and somatotrophic processes such as cell differentiation and proliferation. Also, several highly calcium-dependent tissues such as striated and smooth muscles are not genomic targets for vitamin D. The reviewed data on the diverse and extensive presence of target tissues forecast a high therapeutic potential for vitamin D and especially its low-calcemic analogs, far beyond that which is presently utilized. The evidence provided for vitamin D also testifies to the utility and need to include in vivo cytopharmacology in any target evaluation of bioactive compounds to further the understanding of their mechanisms of action, and to identify preferential targets and their differential therapeutic and toxic potentials.

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“…25(OH)D3 is an active metabolite concerning bone formation and absorption in humans, and it is also converted to lc~,25-dihydroxyvitamin D 3 [Ia,25(OH)2D3] by cytochrome P-450 hydroxylase in the kidney (Gray et al 1972;Hiwatashi et al 1982). lc~,25(OH)2D3 is the most active and hormonal form of vitamin 9 3 and has been used clinically for chronic renal failure, hypoparathyroidism, osteoporosis and psoriasis (Seino et al 1987;DeLuca and Schnoes 1983;Ikekawa Correspondence to: J. Sasaki 1987; Mundy and Roodman 1987). The chemical synthesis of lc~,25(OH)2D3 requires many reaction steps with a very expensive procedure (Kametani and Furuyama 1987).…”

Section: Introductionmentioning

confidence: 99%

Transformation of vitamin D3 to 1?,25-dihydroxyvitamin D3 via 25-hydroxyvitamin D3 using Amycolata sp. strains

Sasaki

Miyazaki

Saito

et al. 1992

Appl Microbiol Biotechnol

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To enzymatically synthesize active metabolites of vitamin D3, we screened about 500 bacterial strains and 450 fungal strains, of which 12 strains were able to convert vitamin D3 to 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] via 25-hydroxyvitamin D3 [25(OH)D3]. The conversion activity was only detected in strains belonging to the genus Amycolata among all the organisms tested. A preparative-scale conversion of vitamin D3 to 25(OH)D3 and 1 alpha,25(OH)2D3 in a 200-1 tank fermentor using A. autotrophica FERM BP-1573 was accomplished, yielding 8.3 mg 25(OH)D3/l culture and 0.17 mg 1 alpha,25(OH)2D3/l culture. A related compound, vitamin D2, could be also converted to 25-hydroxyvitamin D2 and 1 alpha,25-dihydroxyvitamin D2 using the same strain. The cytochrome P-450 of FERM BP-1573 was detected by reduced CO difference spectra in whole-cell suspensions. Vitamin D3 in the culture induced cytochrome P-450 and the conversion activity simultaneously, suggesting that the hydroxylation at C-25 of vitamin D3 and at C-1 of 25(OH)D3 originates from cytochrome P-450.

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Structures and biological activities of vitamin D metabolites and their analogs

Cited by 75 publications

References 208 publications

Association between low levels of 1,25-dihydroxyvitamin D and breast cancer risk

Association between low levels of 1,25-dihydroxyvitamin D and breast cancer risk

Vitamin D sites and mechanisms of action: A histochemical perspective. Reflections on the utility of autoradiography and cytopharmacology for drug targeting

Transformation of vitamin D3 to 1?,25-dihydroxyvitamin D3 via 25-hydroxyvitamin D3 using Amycolata sp. strains

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