Xenobiotic mediated inhibition of hepatic uroporphyrinogen decarboxylase activity in 17-day-old chick embryo liver cells in culture.

Uroporphyrin, heptacarboxylic acid porphyrin and coproporphyrin were the major porphyrins to accumulate when phenobarbital, nifedipine, 3,5-diethoxycarbonyl-2,4,6-trimethylpyridine (Ox-DDC) and 3,3',4,4'-tetrachorobiphenyl (TCBP) were added to chick embryo hepatocyte culture. This pattern of porphyrin accumulation is consistent with the demonstration that these chemicals inhibit uroporphyrinogen decarboxylase (UROG-D). The degree of UROG-D inhibition observed was: TCBP (39%), Ox-DDC (39%), nifedipine (25%) and phenobarbital (50%). Since significant UROG-D inhibition was observed when the bulk of the porphyrins in the crude enzyme preparation was removed by gel filtration, it is unlikely that porphyrins produce the enzyme inhibition. When succinylacetone, a potent inhibitor of delta-aminolevulinic acid dehydratase, was coadministered with Ox-DDC, phenobarbital, TCBP and nifedipine, UROG-D inhibition was not observed. These results suggest that heme biosynthesis must proceed in order for xenobiotic mediated UROG-D inhibition to occur.