Role of COH-SR4 in Xenobiotic Metabolism

Presentation Number: MON 520
Date of Presentation: April 3rd, 2017

Sharad S Singhal*1, James L Figarola1, Jyotsana Singhal1, Samuel Rahbar1, Sulabh Singhal1, David Horne1 and Arthur Riggs2
1Beckman Research Institute of the City of Hope, Duarte, CA, 2Beckman Research Institute of City of Hope, Duarte, CA


Growing evidence indicates that oxidative stress is increased in the diabetic condition due to overproduction of reactive oxygen radicals and decreased efficiency of antioxidant defenses. Glutathione S-transferases (GSTs) are a large, multi-gene family of proteins that may play an important role in protecting tissues from oxidative damage because they function in the transport of cellular components or metabolites (or conjugation of metabolites with glutathione) formed during diabetes. The present study was designed to evaluate the effect of “COH-SR4” on glutathione (GSH)-dependent xenobiotic metabolism and oxidative stress in mice with diabetes. Profound changes in the levels of GSH-linked antioxidant enzymes such as GST, glutathione peroxidase, glutathione reductase, glucose 6-phosphate dehydrogenase and gamma-glutamyl cysteine synthetase, and oxidative stress markers such as lipid hydroperoxides (LOOH) and thiobarbituric acid reactive substances (TBARS) were assessed in the liver of normal and diabetic (db/db) mice with and without treatment with “COH-SR4”. In diabetes mellitus, lipid peroxides formed due to oxidative stress serve as endogenous substrates for GSTs. Mammalian GSTs are highly efficient in the detoxification of these compounds. Lower levels of GSH and GST, and higher levels of oxidative stress markers were found in the diabetic mice. The concentration of malondialdehyde (MDA) measured in the liver of normal mice was 630 ± 103 nmol/g tissue. The changes in the concentration of MDA measured in the liver of db/db mice (2428 ± 235 nmol /g tissue, p < 0.01) and db/db mice treated with SR4 (894 ± 76 nmol /g tissue, p < 0.01) were statistically different from the db/db mice. SR4 feeding to db/db mice (5 mg/kg b.w., 4-weeks treatment on alternate days by oral gavage) significantly decreases oxidative stress markers, brought the level of LOOH and MDA approximately to the level found in control mice, which could be explained by its anti-hyperglycemic effect. GSH concentration was significantly lower of db/db mice compared to control (~ 58%; p < 0.01). Feeding of COH-SR4 to db/db mice markedly increased GSH concentration. These results are consistent with prediction of our model that higher sugar levels caused by lower AMPK expression in db/db mice should result in accumulation of their precursor lipid hydroperoxides and their degradation products. These results suggest that the antioxidant deficiency and excessive peroxide-mediated damage may appear early on in non-insulin-dependent diabetes mellitus, before the development of secondary complications. In conclusion, SR4 is a safe and inexpensive product, causes a significant reduction of the glycation of proteins in diabetic animals. In summary, the present study on the anti-diabetic effects of a novel dichlorophenyl urea compound “COH-SR4” holds great future promise for further development in diabetes treatment.


Nothing to Disclose: SSS, JLF, JS, SR, SS, DH, AR