Effects of Diethyl-1, 4-dihydro-2,4,6-trimethylpyridine-3,5-dicarboxylate on the Metabolism of Porphyrins and Iron

Abstract

Changes in porphyrin metabolism attributable to diethyl-1 ,4dihydro-2,4,6-trimethylpyridine-3,5-dicarboxylate (DTD)’ were first reported by Solomon and Figge in 1959 (I, 2). After the oral administration of the compound to mice and guinea pigs, increased concentrations of liver coproporphyrin and protoporphyrin and renal uroporphyrin and protoporphyrin were observed. Urine analyses revealed increased coproporphyrin, traces of porphobilinogen, and no significant change in uroporphyrin. Such observations on the effects of DTD are of added interest when considered in light of the extensive work that has been done on experimental porphyria induced by Sedormid and related compounds. Recently, comparisons have been made of the changes in porphyrin metabolism due to DTD with alterations found in Sedormidor 2-allyl-2-isopropylacetamide-induced porphyria. The conclusions, which were based largely on porphyrin and precursor excretion patterns, were in disagreement as to the manner in which these different compounds affected porphyrin metabolism. Haeger-Aronsen (3) suggested that DTD-induced porphyria in rabbits differed from Sedormidinduced porphyria, principally in terms of a greater urinary cscretion of &aminolevulinic acid. deMatteis and Prior (4), on the other hand, concluded that the experimental porphyrias induced by DTD and Sedormid in rats were probably indistinguishable. In other reports, concerned primarily with b-aminolevulinic acid synthesis (5, 6), DTD has simply been referred to as a porphyria-inducing agent and is presumed to act like Sedormid and related compounds. However, an examination of the DTD molecule reveals that the essential groupings to induce a 2-allyl-2-isopropylacetamide or Sedormid type of porphyria are absent, and on this basis a different metabolic effect might be expected (7-10). For these reasons, a further investigation of DTD was carried out, but in this instance added emphasis has been placed on metabolism within the liver cell and on subcellular fractions. The results obtained indicate that the inhibition of iron-protoporphyrin chelation is at least one site of action of the compound. Some effects on porphyrin and iron metabolism are compared with those found in 2-allyl-2-isopropylacetamideinduced porphyria.