Metabolic effects of silibinin in the rat liver

Abstract

The flavonolignan silibinin, which is a mixture of two diastereoisomers, silybin A and silybin B, is a component of the extract obtained from the fruit and seeds of the variegated milk thistle (Silybum marianum (L.) Gaertn. (Asteraceae)), known as silymarin. Among the therapeutic properties credited to silibinin, its antihyperglycaemic action has been extensively explored. Silibinin is structurally related to the flavonoids quercetin and fisetin, which have been previously demonstrated to be very active on liver metabolic processes related to glycaemic regulation. The aim of the present work was to investigate the effects of silibinin on metabolic pathways responsible for the maintenance of glycaemia, particularly glycogenolysis and gluconeogenesis, in the perfused rat liver. The activities of some key enzymes in these pathways and on parameters of energy metabolism in isolated mitochondria were also examined. At a concentration range of 50-300μM, silibinin inhibited gluconeogenesis in the fasted condition and inhibited glycogenolysis and glycolysis in the fed condition. The mechanisms by which silibinin exerted these actions were multiple and complex. It inhibited the activity of glucose 6-phosphatase, inhibited the pyruvate carrier, and reduced the efficiency of mitochondrial energy transduction. It can also act by reducing the supply of NADH for gluconeogenesis and mitochondria through its pro-oxidative actions. In general, the effects and the potency of silibinin were similar to those of quercetin and fisetin. However, silibinin exerted some distinct effects such as the inhibitory effect on oxygen consumption in the fed condition and a change in the energy status of the perfused livers. It can be concluded that the effects of silibinin on liver glucose metabolism may explain its antihyperglycaemic property. However, this effect was, in part, secondary to impairment in cellular energy metabolism, a finding that should be considered in its therapeutic usage.

Comparative Effect of Silymarin and D-Penicillamine on Lead Induced Hemotoxicity and Oxidative Stress in Rat

“…On the other hand, there is evidence of antiinflammatory properties of silymarin [24], to which the beneficial impact of this herbal drug on leukocyte counts in the present study can be attributed.…”

“…However, once the oxidative damage is produced by lead, silymarin is almost unable to reverse its consequences. Silymarin ability to act as cellular antioxidant has been attributed to its various beneficial effects including free radical scavenging, reduction of membrane lipid peroxidation and enhancement of GSH reserves [24].…”

Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: A randomized controlled trial

“…More recently, it has been confirmed, in a model of perfused rat liver, that the hepatoprotectant actions of silybin are related to decreased membrane lipid peroxidation, reduced free radical release, and restoration of the glutathione levels [55]. In vivo, in rats, silybin treatment, at doses similar to those used in humans, significantly protected against high-fat-induced fatty liver by stabilizing mitochondrial membrane fluidity, reducing serum content of alanine aminotransferase, decreasing hepatic malondialdehyde, and increasing superoxide dismutase and glutathione levels.…”

Mitochondrial pyruvate transport: a historical perspective and future research directions

“…This inhibition was proposed to be indirect via interaction with the abundant IMM phospholipid cardiolipin, similar to the doxorubicin-mediated inhibition of the mitochondrial phosphate carrier [16]. The antibiotic gatifloxacin also inhibits mitochondrial pyruvate uptake by renal and hepatic mitochondria [17], and silibinin inhibits the MPC in liver mitochondria [18]. Last, it has been reported that zaprinast, a phosphodiesterase inhibitor, blocks mitochondrial pyruvate transport and decreases pyruvate-stimulated oxygen consumption, with no effect on PDH activity [19].…”