Retinoic acid in association with tin-metalloporphyrins influences heme metabolism in vivo in rats

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-pro toporphyrin (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-melloporphyrins with RA: antagonised the Re mediated induction of ALA-S. In the other tissues viz., liver, heart and lung our; results Showed a diminution of ALA-S activity o n RA administration, the, level of repression was further attenuated when t in-metalloporphyrins were do-administered with RA. This marked suppression of ALA-S brought forth by concurrent administration of RA,and tin-metallopo rphyrins is suggestive of;the beneficial effect Of this formulation in acut e attacks Of porphyria, similar to heme. Furthermore, our results emphasize that the combined dosing Of RA with tin-metalloporphyrins leads to a subst antial decline in bilirubin levels: due to; a profound inhibition Of HMOX i n the probed tissues. The features of the combined action of RA and tin-met alloporphyrins in vivo lead to a substantial suppression of formation of th e potentially toxic metabolite bilirubin, and the enhancement Of disposal o f the untransformed substrate (heme) Of the enzyme that is inhibited, These results define Some of the: characteristics of a therapeutically useful fo rmulation and represent a new therapeutic approach far the amelioration and management of hyperbilirubinemia.