γ-Oryzanol

γ-Oryzanol is a potent DNA methyltransferases (DNMTs) inhibitor in the striatum of mice. γ-Oryzanol significantly inhibits the activities of DNMT1 (IC50=3.2 μM), DNMT3a (IC50=22.3 μM).

Signaling Pathways >> Epigenetics >> DNA Methyltransferase

Research Areas >> Metabolic Disease

DNMT1:3.2 μM (IC50)

DNMT3A:22.3 μM (IC50)

γ-Oryzanol significantly inhibits the activities of DNMT1 (IC50=3.2 μM), DNMT 3a (IC50=22.3 μM) and DNMT 3b (maximum inhibition 57%). In contrast, the inhibitory activity of Ferulic acid, a metabolite of γ-Oryzanol, is much lower than that of γ-Oryzanol. Furthermore, γ-Oryzanol acts as a partial antagonist against ERRγ, which primarily serves as a positive regulator for DNMT1 production, and consequently decreased the activity of DNMT1[1].

The brown rice-specific bioactive component γ-Oryzanol, a mixture of ferulic acid ester and several phytosterols, attenuates the preference for dietary fat via a decrease in hypothalamic endoplasmic reticulum (ER) stress. γ-Oryzanol ameliorates HFD-induced DNA hypermethylation of the promoter region of D2R in the striatum of mice. γ-Oryzanol might regulate levels of DNMTs in a striatum-specific manner. γ-Oryzanol partially decreases ERRγ activity (an approximately 40% reduction of the innate value). Oral administration of γ-Oryzanol to male mice by gavage significantly attenuates the preference for an HFD (93% of the values for vehicle-treated mice), resulting in an apparent attenuation of body weight gain[1].

To assess the inhibitory activity of each compound on DNA methylation, the formation of S-adenosyl-l-homocysteine (SAH) is measured in the presence of each compound (20 μM for screening assays),S-adenosyl methionine (SAM; 10 μM) and DNMT substrate (4 ng/μL) at 37°C for 90 min. To evaluate the Michaelis-Menten kinetics, DNMT1 (20 μM) is incubated with γ-Oryzanol, SAM (5 μM) and the indicated concentration of poly dI-dC at 37°C for 90 min. DNMT3a (100 μM) and DNMT3b (100 μM) are incubated with γ-Oryzanol, SAM (5 μM) and the indicated concentration of poly dG•dC at 37°C for 120 min. The assays are performed in quadruplicate. Extracted protein (0.75 mg/mL) is incubated with SAM (5 μM), poly dI-dC (5 μg/mL), and poly dG•dC (5 μg/mL) at 40°C for 120 min, and SAH formation is measured[1].

Mice[1] Seven-week-old male C57BL/6J mice are used. To evaluate the preference for the HFD, γ-Oryzanol is administrated to 8-week-old mice by gavage during the food choice test. For the other experiments, an HFD containing 0.4% γ-Oryzanol is manufactured as pellets. After 12 weeks of feeding, tissue is collected from the striatum and hypothalamus. The daily intake of γ-Oryzanol, estimated from the mean food intake of the mice, is approximately 320 μg/g body weight. The doses of γ-Oryzanol are determined.

[1]. Kozuka C, et al. Impact of brown rice-specific γ-oryzanol on epigenetic modulation of dopamine D2 receptors in brain striatum in high-fat-diet-induced obesity in mice. Diabetologia. 2017 Aug;60(8):1502-1511.

Azacitidine (5-Azacytidine) | SGI 1027 | RG108 | Zebularine | Lomeguatrib | Hinokitiol | DC_517 | DC-05 | Glucose-conjugated MGMT inhibitor

MOLECULAR FORMULA :

C40-H58-O4

MOLECULAR WEIGHT :

602.98

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 :

>25 gm/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

NIIRDN Drugs in Japan (Ethical Drugs). (Yakugyo Jiho Co., Ltd., Tokyo, Japan) Volume(issue)/page/year: -,297,1995

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Administration onto the skin

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

100 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 7,1295,1979

TYPE OF TEST :

LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

1250 mg/kg

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity) Gastrointestinal - hypermotility, diarrhea Skin and Appendages - hair

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 7,2781,1973

TYPE OF TEST :

LD - Lethal dose

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

>1 gm/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 7,2781,1973

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

382 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

NIIRDN Drugs in Japan (Ethical Drugs). (Yakugyo Jiho Co., Ltd., Tokyo, Japan) Volume(issue)/page/year: -,297,1995

TYPE OF TEST :

LD - Lethal dose

ROUTE OF EXPOSURE :

Intramuscular

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

>500 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 7,2781,1973

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

>25 gm/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

NIIRDN Drugs in Japan (Ethical Drugs). (Yakugyo Jiho Co., Ltd., Tokyo, Japan) Volume(issue)/page/year: -,297,1995

TYPE OF TEST :

LD - Lethal dose

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

>10 gm/kg

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity) Gastrointestinal - hypermotility, diarrhea Skin and Appendages - hair

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 7,2781,1973

TYPE OF TEST :

LD - Lethal dose

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

>2500 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 7,2781,1973

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

811 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

NIIRDN Drugs in Japan (Ethical Drugs). (Yakugyo Jiho Co., Ltd., Tokyo, Japan) Volume(issue)/page/year: -,297,1995

TYPE OF TEST :

LD - Lethal dose

ROUTE OF EXPOSURE :

Intramuscular

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

>500 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 7,2781,1973

TYPE OF TEST :

LD - Lethal dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

>5 gm/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 6,2401,1978

TYPE OF TEST :

LD - Lethal dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rabbit

DOSE/DURATION :

>5 gm/kg

TOXIC EFFECTS :

Gastrointestinal - hypermotility, diarrhea

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 6,2401,1978

TYPE OF TEST :

LD - Lethal dose

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rabbit

DOSE/DURATION :

>2500 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 6,2401,1978

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Administration onto the skin

SPECIES OBSERVED :

Rodent - guinea pig

DOSE/DURATION :

100 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 7,1295,1979 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

54300 mg/kg/26W-I

TOXIC EFFECTS :

Related to Chronic Data - death

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 8,3417,1974 ** REPRODUCTIVE DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

36 mg/kg

SEX/DURATION :

female 7-12 day(s) after conception

TOXIC EFFECTS :

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

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 6,1717,1972