The Effect of Dimethyl Sulfoxide on Heme Synthesis and the Acute Phase Reaction in Human HepG2 Hepatoma Cells

Abstract

Heme is an essential prosthetic group for a variety of hemeproteins which are involved in mitochondrial electron transport, microsomal cytochrome P-450-dependent mixed function oxidations and oxygen transport. δ-Amino-levulinic acid (ALA) synthase [succinyl CoA:glycine C-succinyl-transferase(decarboxylating)] (EC 2.3.1.37) is the first enzyme of the heme biosynthetic pathway and catalyzes the condensation of glycine and succinyl CoA to form ALA. ALA synthase activity in the normal rat liver is very low, and is rate-limiting for heme formation. In animal and avian liver cells, the enzyme level is repressed by heme and increased by treatment of animals with porphyrogenic chemicals such as 2-allyl-2-isopropylacetamide and 3,5-diethoxycarbonyl-l, 4-dihydrocollid ine. In contrast to the liver, the regulation of ALA synthase in other tissues appears to be different, and the enzyme activity may not always be rate-limiting for heme formation in non-hepatic tissues, e.g., in erythroid cells^4–8. Little is known about the regulation of ALA synthase and heme synthesis in human liver. For example, it is not known whether the level of ALA synthase in human liver is under feedback control by heme. This is largely because no satisfactory isolated human liver cell preparations have been available for such studies.