| dc.description.abstract | The results presented in this thesis clearly indicate that clofenapate can reproduce the effects of clofibrate on liver weight, mitochondrial content, ubiquinone content and the activities of catalase and glycerol phosphate dehydrogenase. This would point to a common mechanism of action for both these compounds. The greater potency of clofenapate is indicated by the fact that even though it is administered at one hundredth the concentration of clofibrate, the effects are produced practically at the same rate (Chapter IV). Also, when the drug is withdrawn from the diet of the animal, the effects produced by clofenapate persist longer than those produced by clofibrate (Chapter IV). This is consistent with the greater persistence of the drug or its metabolite in the serum (53). From these studies it is expected that clofenapate might prove to be a more effective and popular antihypercholesterolaemic drug than clofibrate.
The studies reported in this thesis permit an objective evaluation of Thorp’s postulation that clofibrate acts by displacing thyroxine from circulation and concentrating it in the liver. The increase in the content of hepatic and renal mitochondria cannot be ascribed to this mechanism because hyperthyroidism does not produce mitochondrial increase in the liver. This is further supported by the observation that while the glycerol phosphate dehydrogenase activity increases in the caudate lobe, the mitochondrial content does not (Chapter VI). However, there are indications that the synthesis and degradation of these organelles are subject to hormonal control. For example, hypophysectomy has been shown to profoundly affect hepatic mitochondrial structure and function (161). Thyroxine has been shown to cause an increase in mitochondrial protein in rat heart though not in liver (152). Also, it is not known whether renal mitochondria increase under hyperthyroidic conditions.
The increase in mitochondrial glycerol phosphate dehydrogenase without any change in the activity of the enzyme in the soluble fraction (Chapter III) is consistent with Thorp’s hypothesis. However, the observation that even though the kidney also becomes presumably hyperthyroidic, the mitochondrial enzyme activity does not increase in the kidney would indicate that other changes which counteract the effects of hyperthyroidism must be simultaneously taking place in the kidney.
The increase in catalase activity in the liver supernatant fraction (Chapter II) is not anticipated by Thorp’s hypothesis because hyperthyroidism decreases the activity of the enzyme. Also, the increase in the enzyme activity is shown by the liver and not by the kidney.
It is clear from the above that Thorp’s hypothesis cannot explain satisfactorily all the effects produced by these drugs on the liver nor can it find satisfactory answers for the differential effects shown by these drugs in liver and kidney. It is quite possible that along with thyroxine other hormones also play a role in mediating these effects. The potentiation of the effects of insulin (32) and the effects of these drugs on adenyl cyclase and cyclic AMP levels (51) would indicate such possibilities. Recent reports from the laboratory of Porter (165–165) indicate that the metabolism of cholesterol is controlled by thyroxine, insulin, glucagon, hydrocortisone and possibly other hormones elaborated by the pituitary.
The striking and impressive increase in liver weight and microbodies has prompted Steinberg (37) to suggest that the primary effect of clofibrate may be on the cell membranes. Alteration of membrane permeability would profoundly affect metabolism, and other changes taking place may be secondary to this.
Administration of these drugs offers a good system to study mammalian mitochondriogenesis. The fact that along with mitochondria, peroxisomes also proliferate in the liver would make this system quite useful for the verification of the hypothesis of Rouiller & Bernhard (28) that peroxisomes represent a stage in the biosynthesis of mitochondria. | |
