Tibolone impairs glucose and fatty acid metabolism and induces oxidative stress in livers from female rats

Abstract

Tibolone is a synthetic steroid that has been extensively prescribed to treat climacteric symptoms and to prevent postmenopausal osteoporosis. Because menopause is a condition associated with increased incidence of metabolic disturbances and hepatic steatosis, the aim of this work was to evaluate the actions of tibolone on the liver. The effects of tibolone on glucose and fatty acid metabolism and on several parameters linked to mitochondrial energy metabolism, including the induction of cellular oxidative stress, were investigated in livers from female Wistar rats. Tibolone was assayed at concentrations ranging from 5 to 100μM. In perfused livers, tibolone inhibited oxygen uptake, stimulated glycogenolysis and glycolysis, and inhibited gluconeogenesis from l-lactate and ketogenesis from exogenous octanotate. Tibolone also caused pronounced increases in both the cytosolic and mitochondrial NADH/NAD+ratios. In isolated mitochondria, tibolone inhibited oxygen uptake due to β-hydroxybutyrate and fatty acid oxidation without affecting the succinate oxidation. The inhibitory action of tibolone at complex I of the mitochondrial respiratory chain was suggested by the inhibition of the NADH-oxidase activity. Tibolone also induced oxidative stress in both perfused livers and isolated mitochondria, as indicated by the increased production of thiobarbituric acid reactive substances. These metabolic alterations may increase the risk of metabolic disturbances during tibolone administration, particularly in the postmenopausal condition.