Orotic acid (OA) is an intermediate in pyrimidine metabolism.IC50 Value: Target: Nucleoside antimetabolite/analogin vitro: OA increases cell proliferation and decreases apoptosis in serum-starved SK-Hep1 hepatocellular carcinoma cells, which may ascribe to the inhibition of AMP-activated protein kinase (AMPK) phosphorylation and thus activation of mammalian target of rapamycin complex 1 (mTORC1) [1].in vivo: male Fischer 344 rats (130-150 g) to two-thirds PH in the absence or in the presence of OA (a 300-mg tablet of OA methyl ester implanted intraperitoneally at the time of two-thirds PH). treatment with OA resulted in a near-100% inhibition of RNR induced by two-thirds PH in rat liver, as monitored by enzyme activity and protein level [2]. The increases of hepatic OA and betaine levels in OA feeding rats was also found when compared to the normal rats [3]. Feeding 1% OA with diet decreased the phosphorylation of AMPK and increased the maturation of SREBP-1 and the expression of SREBP-responsive genes in the rat liver. OA-induced lipid accumulation was also completely inhibited by rapamycin. Mouse hepatocytes and mice were resistant to OA-induced lipogenesis because of little if any response in AMPK and downstream effectors [4].
References:
[1]. Jung, E.J., K.Y. Lee, and B.H. Lee, Proliferating effect of orotic acid through mTORC1 activation mediated by negative regulation of AMPK in SK-Hep1 hepatocellular carcinoma cells. J Toxicol Sci, 2012. 37(4): p. 813-21.
[2]. Manjeshwar, S., et al., The regulation of ribonucleoside diphosphate reductase by the tumor promoter orotic acid in normal rat liver in vivo. Mol Carcinog, 1999. 24(3): p. 188-96.
[3]. Cha, J.Y., et al., Effect of betaine on the hepatic damage from orotic acid-induced fatty liver development in rats. J Enzyme Inhib Med Chem, 2011.
[4]. Jung, E.J., et al., Role of the AMPK/SREBP-1 pathway in the development of orotic acid-induced fatty liver. J Lipid Res, 2011. 52(9): p. 1617-25.