A Possible Role of Copper in the Regulation of Heme Biosynthesis Through Ferrochelatase

Abstract

Drugs and heavy metals may alter the synthesis of hemo-proteins by either inducing or inhibiting various enzymes in the heme biosynthetic pathway (Fig. 1) (Tephly et al., 1971; Tephly et al., 1973). Porphyrogenic drugs and inducers of the hepatic hemo-protein, cytochrome P-450, such as phenobarbital, induce hepatic δ-aminolevulinic acid synthetase (ALAS), the initial and proposed rate-limiting enzyme of this pathway (Granick and Urata, 1963; Baron and Tephly, 1969; Tephly et al., 1973). Ferrochelatase (heme synthetase, protoheme ferro-lyase, EC 4.99.1.1), the terminal enzyme in the heme pathway, is located on the inner mitochondrial membrane (Jones and Jones, 1968; McKay et al., 1969) and catalyzes the formation of heme from protoporphyrin IX and ferrous iron (Labbe and Hubbard, 1960). This enzyme, like ALAS, is inducible (Hasegawa et al., 1970; Tephly et al., 1971), and may be subject to product inhibition by heme (Jones and Jones, 1970). Heme which is formed through ferrochelatase is then available for synthesis of cytochrome P-450 and other hemoproteins. Tephly and co-workers (Tephly and Hibbeln, 1971; Tephly et al., 1972) have reported that cobalt treatment produces a substantial decrease in the level of hepatic cytochrome P-450.