Calcipotriene

Calcipotriol is a synthetic VitD3 analogue with a high affinity for the vitamin D receptor.

Signaling Pathways >> Vitamin D Related >> VD/VDR

Research Areas >> Inflammation/Immunology

Vitamin D receptor[1]

When NHEK cells are not stimulated with IL-17A or IL-22, Calcipotriol slightly enhances (0.2 nM) IL-8 mRNA expression or has no effect (2-20 nM). The addition of IL-17A and IL-22 markedly increased the mRNA expression of IL-8, confirming our previous study. This enhanced IL-8 mRNA expression is suppressed by Calcipotriol at 2, 20 and 40 nM in a dose dependent manner[1]. Treatment of natural killer (NK) cells with drugs modulates their expression of NK cytotoxicity receptors or KIR. Human NK cells are pre-treated with 100, 10 or 1 ng/mL of 1,25(OH)2D3, Calcipotriol or FTY720 for 4 h. All three concentrations of 1,25(OH)2D3, Calcipotriol and FTY720 significantly up-regulate the expression of NKp30 on the surface of NK cells after 4 h incubation[2].

One out of the 32 animals in each of the groups has died, except for the Diclofenac plus DFMO plus Calcipotriol group, where all animals survived. Survival is equally distributed between the groups. The weight gain is significantly smaller in the groups treated with Diclofenac plus Calcipotriol (p=0.018) and Diclofenac plus DFMO plus Calcipotriol (p=0.002) compare with placebo (linear regression model)[3].

Normal human epidermal keratinocytes (NHEK) are grown in serum-free keratinocyte growth medium Epilife and used at third passage in all experiments. Growth supplement is omitted 48 h before experiments. As a control, IL-17A and IL-22 are either added or not added to the cells. Cultured NHEK cells are stimulated with IL-17A (200 ng/mL) and/or IL-22 (200 ng/mL) followed by co-incubation in the presence or absence of Calcipotriol at 0.2-40 nM to test its modulatory effect. Cells are harvested 3 days later and subjected to real-time quantitative PCR (qPCR). Culture supernatants are also collected and frozen at -80°C until use for ELISA[1].

Mice[3] The 160 female SKH-1 hairless mice (6-7 weeks of age) are used. After UV treatment, mice without tumors are randomly divided into five groups, four chemoprevention groups (Diclofenac plus DFMO; Diclofenac plus Calcipotriol; DFMO plus calcitriol; and Diclofenac plus DFMO plus Calcipotriol) and one placebo group (skin lotion). The placebo group used in this study is the same as the one used in an earlier study. The mice are treated with test mixtures once a day, five days a week, for a total of 17 weeks. The test mixtures are applied topically on the dorsal surface of the mice. Ten microliters are applied by a pipette after which the mixture is rubbed onto the skin. This corresponded to the following doses of each active substance in the treatments: 100 μg/week for Diclofenac (30 mg/g undiluted), 0.166 μg/week for Calcitriol (50 μg/g undiluted), and 463.3 μg/week for difluoromethylornithine (DFMO) (139 mg/g undiluted).

[1]. Sakabe JI, et al. Calcipotriol Increases hCAP18 mRNA Expression but Inhibits Extracellular LL37 Peptide Production in IL-17/IL-22-stimulated Normal Human Epidermal Keratinocytes. Acta Derm Venereol. 2014 Sep;94(5):512-6.

[2]. Al-Jaderi Z, et al. Effects of vitamin D3, calcipotriol and FTY720 on the expression of surface molecules and cytolytic activities of human natural killer cells and dendritic cells. Toxins (Basel). 2013 Oct 28;5(11):1932-47.

[3]. Pommergaard HC, et al. Combination chemoprevention with diclofenac, calcipotriol and difluoromethylornithine inhibits development of non-melanoma skin cancer in mice. Anticancer Res. 2013 Aug;33(8):3033-9.

[4]. Reinhard Bredehorst, et al. Induction of Antigen-Specific Tolerance by Peripheral Phagocytosis. US 20150283231 A1.

[5]. Kaur A, et al. Nanoemulsion loaded gel for topical co-delivery of clobitasol propionate and calcipotriol in psoriasis. Nanomedicine. 2017 May;13(4):1473-1482.

Maxacalcitol | Paricalcitol | Vitamin D3 | 25-Hydroxycalciferol | Calcipotriol (monohydrate) | 3-O-(2-Aminoethyl)-25-hydroxyvitamin D3 | Secalciferol | Seocalcitol | 25,26-Dihydroxyvitamin D3 | Calcitetrol | Eldecalcitol | Ergocalciferol | Vitamin D4 | 24, 25-Dihydroxy VD2 | Calcipotriol Impurity C

MOLECULAR FORMULA :

C27-H40-O3

MOLECULAR WEIGHT :

412.67

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Administration onto the skin

SPECIES OBSERVED :

Human - woman

DOSE/DURATION :

10 gm/kg/6W-I

TOXIC EFFECTS :

Nutritional and Gross Metabolic - changes in calcium

REFERENCE :

BMJOAE British Medical Journal. (British Medical Assoc., BMA House, Tavistock Sq., London WC1H 9JR, UK) V.1- 1857- Volume(issue)/page/year: 306,896,1993

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Administration onto the skin

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

11 gm/kg/11W-I

TOXIC EFFECTS :

Nutritional and Gross Metabolic - changes in calcium

REFERENCE :

BMJOAE British Medical Journal. (British Medical Assoc., BMA House, Tavistock Sq., London WC1H 9JR, UK) V.1- 1857- Volume(issue)/page/year: 306,896,1993

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Administration onto the skin

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

>15 mg/kg

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity) Behavioral - ataxia Nutritional and Gross Metabolic - weight loss or decreased weight gain

REFERENCE :

JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 21(Suppl 2),277,1996

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

2190 ug/kg

TOXIC EFFECTS :

Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - dyspnea Gastrointestinal - hypermotility, diarrhea

REFERENCE :

JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 21(Suppl 2),277,1996

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Administration onto the skin

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

>1500 ug/kg

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity) Gastrointestinal - nausea or vomiting Musculoskeletal - other changes

REFERENCE :

JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 21(Suppl 2),277,1996 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Administration onto the skin

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

560 ug/kg/4W-I

TOXIC EFFECTS :

Sense Organs and Special Senses (Eye) - corneal damage Kidney, Ureter, Bladder - other changes in urine composition Nutritional and Gross Metabolic - changes in calcium

REFERENCE :

JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 21(Suppl 2),287,1996

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

364 ug/kg/26W-I

TOXIC EFFECTS :

Kidney, Ureter, Bladder - changes in bladder weight Blood - changes in serum composition (e.g. TP, bilirubin, cholesterol) Nutritional and Gross Metabolic - changes in calcium

REFERENCE :

JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 21(Suppl 2),325,1996

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Administration onto the skin

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

728 ug/kg/26W-I

TOXIC EFFECTS :

Kidney, Ureter, Bladder - other changes in urine composition Skin and Appendages - dermatitis, other (after systemic exposure) Nutritional and Gross Metabolic - changes in calcium

REFERENCE :

JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 21(Suppl 2),365,1996 ** REPRODUCTIVE DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

275 ug/kg

SEX/DURATION :

female 7-17 day(s) after conception

TOXIC EFFECTS :

Reproductive - Maternal Effects - other effects Reproductive - Specific Developmental Abnormalities - musculoskeletal system

REFERENCE :

JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 21(suppl 2),403,1996

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

650 ug/kg

SEX/DURATION :

female 17-21 day(s) after conception lactating female 21 day(s) post-birth

TOXIC EFFECTS :

Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain)

REFERENCE :

JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 21(suppl 2),439,1996

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

13 ug/kg

SEX/DURATION :

female 6-18 day(s) after conception

TOXIC EFFECTS :

Reproductive - Maternal Effects - other effects Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured before birth)

REFERENCE :

JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 21(suppl 2),425,1996