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

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 100 µM. 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 ß-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.

Glucose and glycogen catabolism in perfused livers of Walker-256 tumor-bearing rats and the response to hormones.

The alterations in hepatic glucose and glycogen catabolism were evaluated in rats bearing the Walker-256 tumor. Food intake was monitored concomitantly with measurements of the in vivo hepatic glycogen levels. Glycogenolysis, glycolysis and oxygen uptake were measured in the isolated perfused liver. The hepatic glucose phosphorylating capacity was measured in the high-speed supernatant fraction of liver homogenates. Food intake was 21.4% reduced in tumor-bearing rats; the glycogen levels were decreased by 63.6%. Initial basal rates of glucose release (glycogenolysis) and lactate+pyruvate production from endogenous glycogen (glycolysis) in the perfused liver were not changed by the tumor-bearing state, resulting in a higher relative rate of glycogen breakdown (% of glycogen degradation per unit time). In absolute terms stimulation of glycogen mobilization by glucagon or norepinephrine was smaller in the tumor-bearing state. The percentage of extra glycogen degradation per unit time caused by both hormones, however, was practically the same in the control and in the tumor-bearing state. The hepatic glucose phosphorylating capacity was reduced from 3.92+/-0.39 nmolmin(-1)(mgprotein)(-1) in normal rats to 2.61+/-0.23 nmolmin(-1)(mgprotein)(-1) in livers from tumor-bearing rats. Glycolysis from exogenous glucose (20 mM) in perfused livers was diminished from 0.136+/-0.023 &mgr;molmin(-1)(gliver)(-1) in normal rats to 0.046+/-0.008 &mgr;molmin(-1)(gliver)(-1) in tumor-bearing rats. It can be concluded that livers from rats bearing the Walker-256 tumor are less able to transform glucose and accumulate glycogen while possessing a greater tendency of releasing glucose from the glycogen stores.