METALSINMEDICINE 423

F046 Alteration in Heme Biosynthetic Pathway by Synthetic Hetal Porphyrins.

Ramesh Chandra, Ripla Beri and Mukta Dhawan Chemistry Dept., Delhi University, Delhi-1100 07

Enzymes which are normally present in excess in the heme biosynthetic pathway may become rate-limiting for heme formation if their activities are markedly impaired. In the liver, heme regulates its own biosynthesis in a feedback fashion. When sufficient amounts of heme are made for mitochondrial and microsomal cytochromes, heme represses the synthesis of s-aminolevulinic acid (ALA) synthase, thus reducing further increase in heme synthesis. ALA-synthase is of clinical interest because the biochemical defect associated with the autosomal dominant genetic disease acute intermittent porphyria (AIP) some times produces induction of enzyme activity in affected individuals, [l] with consequent neurological impairments attributed to some intermediate of the activated heme pathway.

We have studied in detail the ability in vivo of synthetic metalloporphyrins to both inhibit and induce ALA-synthase activity in Wistar rats, thus altering hepatic heme biosynthetic pathway. It is manifested by marked changes in cellular functions dependent on heme. Co-PP decreases in a marked and sustained manner, the activity of ALA-synthase. The perturbations in ALA-synthase are characterized by an early depression of enzyme activity followed by a "rebound" phenomenon. Inducing action of some inorganic metals can be blocked by others. Manganese and Zinc when administered simultaneously with tin alters the ALA-synthase activity associated with tin administration [2]. Animals when given PP-IX and bilirubin alone and in combination with Sn-PP and heme in male and female neonatal rats, ALA-synthase activity was induced more in females as compared to males [2].

1. S. Sassa, H. Fujita and A. Kappas Highlights Modern Biochem., 1, 329-338, (1989)

2. Ripla Beri and Ramesh Chandra Drug Metab. Revs., 25(1&2), 49-152, (1993)