Calcitriol

Calcitriol is the most active metabolite of vitamin D and also a vitamin D receptor (VDR) agonist.

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

Research Areas >> Cancer

Natural Products >> Others

Human Endogenous Metabolite

Calcitriol exerts antiproliferative effects on cervical cancer cells in vitro. Cells decrease by 12.8% when treated with 100 nM Calcitriol for 6 days, compare with control. Inhibition of cell proliferation becomes more pronounced with the increase in Calcitriol concentration. The decrease is 26.1% and 31.6% for 200 and 500 nM Calcitriol, respectively. Treatment with Calcitriol for 72 h induces an evident accumulation of cells in the G1 phase, with approximately 66.18% in 200 nM and 78.10% in 500 nM, compare with the control (24.36%). Calcitriol treatment significantly decreases HCCR-1 protein expression compare with the control in a time- and dose-dependent manner[1]. Calcitriol significantly increases ERα mRNA in a dose dependent manner with an EC50 of 9.8×10-9 M[2].

Chronic treatment with Calcitriol (150 ng/kg per day for 4.5 months) improves the relaxations (pD2: 6.30±0.09, Emax: 68.6±3.9% in Calcitriol-treated OVX, n=8). Renal blood flow in OVX rats is reduced in both kidneys, and the flow is restored by Calcitriol treatment. The increased expression of COX-2 and Thromboxane-prostanoid (TP) receptor in OVX rat renal arteries is reduced by chronic calcitriol administration[3]. High- and low-dose Calcitriol treatment significantly decreases the systolic blood pressure (SBP) in the fructose-fed rats by 14±4 and 9±4 mmHg, respectively, at Day 56. High-dose Calcitriol treatment (20 ng/kg per day) significantly increases serum ionized calcium level (1.44±0.05 mmol/L) compare with the other groups[4].

HeLa S3 cells are plated at a density of 1,000 cells/well in 96-well plates of Dulbecco’s modified Eagle’s medium (DMEM) with 10% fetal bovine serum (FBS), treated with 1% ethanol (control) or various concentrations of Calcitriol (100, 200, and 500 nM) for 72 h. A Cell Counting Kit8 (CCK-8) is used to determine cell proliferation. At 24, 48, 72, 96, 120, and 144 h after culturing with 200 nM Calcitriol, cells are harvested for analysis. Three independent experiments are performed in quadruplicate[1].

Adult female Sprague-Dawley rats weighing 200 to 220g are used in this study. Rats are housed in a temperature-controlled room (~23°C) with a 12-h light/dark cycle. The animals have free access to a standard diet and water. Ovariectomy (OVX) is performed on rats. At 6 months after the surgical procedure, the OVX rats are randomly assigned to either treatment with vehicle dimethyl sulfoxide (OVX+vehicle) or Calcitriol (150 ng/kg daily, OVX+calcitriol). Calcitriol treatment is given by oral gavage and lasted or 4.5 months. Blood pressure and serum Calcitriol level are measured[3].

[1]. Wang G, et al. Calcitriol Inhibits Cervical Cancer Cell Proliferation Through Downregulation of HCCR1 Expression. Oncol Res. 2014;22(5-6):301-9.

[2]. Santos-Martínez N, et al. Calcitriol restores antiestrogen responsiveness in estrogen receptor negative breast cancer cells: a potential new therapeutic approach. BMC Cancer. 2014 Mar 29;14:230.

[3]. Dong J, et al. Calcitriol restores renovascular function in estrogen-deficient rats through downregulation of cyclooxygenase-2 and the thromboxane-prostanoid receptor. Kidney Int. 2013 Jul;84(1):54-63.

[4]. Chou CL, et al. Beneficial effects of calcitriol on hypertension, glucose intolerance, impairment of endothelium-dependent vascular relaxation, and visceral adiposity in fructose-fed hypertensive rats. PLoS One. 2015 Mar 16;10(3):e0119843.

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MOLECULAR FORMULA :

C27-H44-O3

MOLECULAR WEIGHT :

416.71

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

620 ug/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

>5 mg/kg

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity) Gastrointestinal - hypermotility, diarrhea Kidney, Ureter, Bladder - other changes

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

66 ug/kg

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity) Behavioral - ataxia Nutritional and Gross Metabolic - body temperature decrease

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

105 ug/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

1350 ug/kg

TOXIC EFFECTS :

Sense Organs and Special Senses (Eye) - lacrimation Behavioral - ataxia Nutritional and Gross Metabolic - body temperature decrease

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

1900 ug/kg

TOXIC EFFECTS :

Sense Organs and Special Senses (Eye) - lacrimation Behavioral - ataxia Nutritional and Gross Metabolic - body temperature decrease

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

145 ug/kg

TOXIC EFFECTS :

Sense Organs and Special Senses (Eye) - lacrimation Behavioral - ataxia Nutritional and Gross Metabolic - body temperature decrease

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

35 ug/kg/5W-I

TOXIC EFFECTS :

Kidney, Ureter, Bladder - changes in bladder weight Endocrine - changes in adrenal weight Blood - changes in serum composition (e.g. TP, bilirubin, cholesterol)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

13650 ng/kg/13W-I

TOXIC EFFECTS :

Kidney, Ureter, Bladder - interstitial nephritis Nutritional and Gross Metabolic - weight loss or decreased weight gain Nutritional and Gross Metabolic - changes in potassium

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

35100 ng/kg/26W-I

TOXIC EFFECTS :

Sense Organs and Special Senses (Eye) - conjunctive irritation Kidney, Ureter, Bladder - changes in bladder weight Biochemical - Metabolism (Intermediary) - other proteins

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

9100 ng/kg/13W-I

TOXIC EFFECTS :

Behavioral - food intake (animal) Nutritional and Gross Metabolic - weight loss or decreased weight gain Related to Chronic Data - death

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

19960 ng/kg/52W-I

TOXIC EFFECTS :

Behavioral - food intake (animal) Kidney, Ureter, Bladder - interstitial nephritis Nutritional and Gross Metabolic - weight loss or decreased weight gain

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

55 ug/kg

SEX/DURATION :

female 7-17 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

15 ug/kg

SEX/DURATION :

female 16-21 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) Reproductive - Specific Developmental Abnormalities - musculoskeletal system Reproductive - Specific Developmental Abnormalities - blood and lymphatic systems (including spleen and marrow)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

DOSE :

9450 ng/kg

SEX/DURATION :

female 3 week(s) pre-mating

TOXIC EFFECTS :

Reproductive - Maternal Effects - ovaries, fallopian tubes Reproductive - Maternal Effects - uterus, cervix, vagina Reproductive - Maternal Effects - other effects

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

DOSE :

11550 ug/kg

SEX/DURATION :

male 9 week(s) pre-mating female 2 week(s) pre-mating

TOXIC EFFECTS :

Reproductive - Fertility - pre-implantation mortality (e.g. reduction in number of implants per female; total number of implants per corpora lutea) Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

DOSE :

11550 ug/kg

SEX/DURATION :

male 9 week(s) pre-mating female 2 week(s) pre-mating

TOXIC EFFECTS :

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

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

DOSE :

4950 ug/kg

SEX/DURATION :

female 7-17 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Parenteral

DOSE :

15 ug/kg

SEX/DURATION :

female 16-21 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - musculoskeletal system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

104 ng/kg

SEX/DURATION :

female 6-18 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - musculoskeletal system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

520 ng/kg

SEX/DURATION :

female 6-18 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants)

MUTATION DATA

TYPE OF TEST :

Unscheduled DNA synthesis

TEST SYSTEM :

Rodent - mouse Cells - not otherwise specified

DOSE/DURATION :

5 ug/L

REFERENCE :

CNREA8 Cancer Research. (Public Ledger Building, Suit 816, 6th & Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- Volume(issue)/page/year: 46,5582,1986 *** NIOSH STANDARDS DEVELOPMENT AND SURVEILLANCE DATA *** NIOSH OCCUPATIONAL EXPOSURE SURVEY DATA : NOES - National Occupational Exposure Survey (1983) NOES Hazard Code - X4899 No. of Facilities: 8 (estimated) No. of Industries: 1 No. of Occupations: 1 No. of Employees: 239 (estimated) No. of Female Employees: 157 (estimated)