Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd.
Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University.
J Toxicol Sci. 2021;46(1):31-42. doi: 10.2131/jts.46.31.
Nonalcoholic fatty liver disease, which has been rapidly increasing in the world in recent years, is roughly classified into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis. This study was based on our previous reports that stated that the combination treatment of N-methylnicotinamide (MNA) and hydralazine (HYD) improves fatty liver in NAFL model rats. This finding was attributed to the MNA metabolism inhibition by HYD, which is a strong inhibitor of aldehyde oxidase (AO); this results in an increase in hepatic MNA and improved fatty liver. We hypothesized that orally administered nicotinamide (NAM), which is the precursor of MNA and is a form of niacin, would be efficiently metabolized by nicotinamide N-methyltransferase in the presence of exogenous S-adenosylmethionine (SAM) in NAFL rats. To address this issue, NAFL model rats were orally administered with NAM, SAM, and/or HYD. As a result, liver triglyceride (TG) and lipid droplet levels were barely altered by the administration of NAM, SAM, NAM+SAM, or NAM+HYD. By contrast, the triple combination of NAM+SAM+HYD significantly reduced hepatic TG and lipid droplet levels and significantly increased hepatic MNA levels. These findings indicated that the combination of exogenous SAM with AO inhibitors, such as HYD, has beneficial effects for improving fatty liver with NAM.
非酒精性脂肪性肝病（NAFLD）近年来在世界范围内迅速增加，大致可分为非酒精性脂肪肝（NAFL）和非酒精性脂肪性肝炎。本研究基于我们之前的报告，即 N-甲基烟酰胺（MNA）和肼屈嗪（HYD）联合治疗可改善 NAFL 模型大鼠的脂肪肝。这一发现归因于 HYD 对 MNA 代谢的抑制作用，HYD 是醛氧化酶（AO）的强抑制剂；这导致肝内 MNA 增加并改善脂肪肝。我们假设，在存在外源性 S-腺苷甲硫氨酸（SAM）的情况下，口服烟酰胺（NAM），它是 MNA 的前体，也是烟酰胺的一种形式，将在 NAFL 大鼠中被烟酰胺 N-甲基转移酶有效地代谢。为了解决这个问题，我们给 NAFL 模型大鼠口服给予 NAM、SAM 和/或 HYD。结果表明，NAM、SAM、NAM+SAM 或 NAM+HYD 的给药对肝甘油三酯（TG）和脂质滴水平几乎没有改变。相比之下，NAM+SAM+HYD 的三联组合显著降低了肝 TG 和脂质滴水平，并显著增加了肝 MNA 水平。这些发现表明，外源性 SAM 与 AO 抑制剂（如 HYD）的组合对改善 NAM 引起的脂肪肝具有有益作用。
