Dual mechanism of inhibition of rat liver uroporphyrinogen decarboxylase activity by ferrous iron: its potential role in the genesis of porphyria cutanea tarda.

Hepatic iron overload amplifies the uroporphyrinogen decarboxylase enzyme defect in human porphyria cutanea tarda. To understand its mechanism, we studied the effects of iron on the enzyme activity from rat liver cytosol. Enzyme activity was inhibited about 50% by 0.10 mM Fe2+ or by 0.16 mM Zn2+ directly regardless of whether the cations were added immediately, or were first preincubated for 2 h at 37 degrees C in the absence or presence of oxygen. Cysteine (6.7 mM) protected the enzyme from inhibition by Fe2+ under strictly anaerobic preincubation conditions; cysteine also protected enzyme inhibition by Zn2+ even in the presence of oxygen. Under aerobic conditions, cysteine enhanced the inhibition by Fe2+ to about 70%. This additional 20% inhibition was reversed by vitamin E, an antioxidant. The results suggest dual inhibitory effects of iron (a) by direct interaction of Fe2+, as well as Zn2+, with the essential sulfhydryl group(s) of the enzyme and (b), indirectly, due to generation of free radicals in the presence of oxygen and an electron donor such as cysteine. These radicals might interact directly with the enzyme and/or oxidize the porphyrinogen substrates to nonmetabolizable porphyrins, which accumulate in porphyric patients.