Raloxifene affects fatty acid oxidation in livers from ovariectomized rats by acting as a pro-oxidant agent

Abstract

Estrogen deficiency accelerates the development of several disorders including visceral obesity and hepatic steatosis. The predisposing factors can be exacerbated by drugs that affect hepatic lipid metabolism. The aim of the present work was to determine if raloxifene, a selective estrogen receptor modulator (SERM) used extensively by postmenopausal women, affects hepatic fatty acid oxidation pathways. Fatty acids oxidation was measured in the livers, mitochondria and peroxisomes of ovariectomized (OVX) rats. Mitochondrial and peroxisomal β-oxidation was inhibited by raloxifene at a concentration range of 2.5-25 μM. In perfused livers, raloxifene reduced the ketogenesis from endogenous and exogenous fatty acids and increased the β-hydroxybutyrate/acetoacetate ratio. An increase in ¹⁴CO₂ production without a parallel increase in the oxygen consumption indicated that raloxifene caused a diversion of NADH from the mitochondrial respiratory chain to another oxidative reaction. It was found that raloxifene has a strong ability to react with H₂O₂ in the presence of peroxidase. It is likely that the generation of phenoxyl radical derivatives of raloxifene in intact livers led to the co-oxidation of NADH and a shift of the cellular redox state to an oxidised condition. This change can perturb other important liver metabolic processes dependent on cellular NADH/NAD⁺ ratio.

Review article: drug‐induced liver injury in the context of nonalcoholic fatty liver disease – a physiopathological and clinical integrated view

“…Even though all the aforementioned alterations can occur in a healthy liver, it has also been reported that a pre‐existing fatty liver, or even only risk factors for this condition, may contribute to a higher incidence of advanced forms of fatty liver disease caused by certain drugs. An example is the development and worsening of the hepatic steatosis caused by the oestrogen receptor modulators tamoxifen and raloxifene, via impairment of both mitochondrial function and FFA β‐oxidation, as well as stimulation of the de novo FFA synthesis . In these cases, obesity and other metabolic risk factors have been identified as independent predictors …”

Fructose and Uric Acid: Is There a Role in Endothelial Function?

“…In contrast, gonadectomized male rats fed a high fructose diet did not develop hypertension, suggesting that testosterone may act as a causal link between insulin resistance/hyperinsulinemia and hypertension, and it is the absence of testosterone that prevented the development of fructose-induced hypertension [49]. In general, physiological concentrations of estrogen have beneficial effects on lipoproteins, insulin, and glucose metabolism [50]. Estrogen can improve insulin action in the liver, muscle, and adipose tissue by increasing glycogen deposition, glucose uptake, and lipogenesis [51].…”

Drug-Induced Inhibition of Mitochondrial Fatty Acid Oxidation and Steatosis

“…Interestingly, inhibition of mtFAO has been documented with several of these drugs, namely tamoxifen, raloxifene and NRTIs [3,28,93,94]. Moreover, drugs such as tamoxifen, methotrexate and NRTIs can inhibit MRC activity and favor oxidative stress [3,16,28,95,96].…”