tretinoin and tin-mesoporphyrin

Retinol (Vitamin A) is known to destabilize membranes. The effect of one of its natural derivatives, Retinoic Acid, was therefore studied on membrane stability, by inversely correlating this stability with Phospholipase A(2) activity. Lipid metalloporphyrin interactions have been the object of intense research in recent times. Our results revealed that the administration of Retinoic Acid (50,000 I.U.) caused a tremendous induction of hepatic Phospholipase A(2) activity in Wistar rats. However when Retinoic Acid and Tin-mesoporphyrin (50 micromol/kgbw) were co-administered, hepatic Phospholipase A(2) activity was inhibited. This result clearly reveals a possible therapeutic application of this metalloporphyrin in alleviating membrane destabilization, connected with Retinoic acid administration.

Topics: Animals; Cell Membrane; Cell Membrane Permeability; Enzyme Inhibitors; Liver; Membrane Proteins; Metalloporphyrins; Molecular Structure; Phospholipases A; Rats; Rats, Wistar; Tretinoin

In the current study we report the perturbation of key enzymes of the heme metabolic pathway, i.e. delta-amino levulinic acid synthase, heme oxygenase and biliverdin reductase, in vivo by administration of retinoic acid (RA) and retinoic acid in association with tin-metalloporphyrins, viz., tin-protoporphyrin (SnPP) and tin-mesoporphyrin (SnMP) in the liver, spleen, heart and lung of rats. RA at a dosing regimen of 50,000 I.U. stimulated splenic ALA-S activity, whereas co-administration of tin-metalloporphyrins with RA antagonised the RA mediated induction of ALA-S. In the other tissues viz., liver, heart and lung our results showed a diminution of ALA-S activity on RA administration, the level of repression was further attenuated when tin-metalloporphyrins were co-administered with RA. This marked suppression of ALA-S brought forth by concurrent administration of RA and tin-metalloporphyrins is suggestive of the beneficial effect of this formulation in acute attacks of porphyria, similar to heme. Furthermore, our results emphasize that the combined dosing of RA with tin-metalloporphyrins leads to a substantial decline in bilirubin levels due to a profound inhibition of HMOX in the probed tissues. The features of the combined action of RA and tin-metalloporphyrins in vivo lead to a substantial suppression of formation of the potentially toxic metabolite bilirubin, and the enhancement of disposal of the untransformed substrate (heme) of the enzyme that is inhibited. These results define some of the characteristics of a therapeutically useful formulation and represent a new therapeutic approach for the amelioration and management of hyperbilirubinemia.

Topics: 5-Aminolevulinate Synthetase; Animals; Bilirubin; Drug Interactions; Enzyme Inhibitors; Heme; Heme Oxygenase (Decyclizing); Liver; Lung; Male; Metalloporphyrins; Myocardium; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Proteins; Protoporphyrins; Rats; Rats, Wistar; Spleen; Tretinoin