Toxicity of polychlorinated biphenyl with special reference to porphyrin metabolism.
Oral administration of a commercial PCB mixture to chickens caused a hepatic-type porphyria characterized by hepatic accumulation and urinary excretion of uroporphyrin. To clarify the mechanism of the porphyrinogenic activity of these PCBs, we studied the structural requirement of synthetic PCB for porphyrinogenic activities by using the cultured chick embryo liver cells and examined the relationship between induction of delta-aminolevulinic acid (ALA) synthetase and inhibition of uroporphyrinogen decarboxylase. We established that the porphyrinogenic effect of PCBs exhibits a sharply defined structure-activity relationship in that only 3,4,3',4'-tetrachlorobiphenyl and 3,4,5,3',4',5'-hexachlorobiphenyl produced a marked accumulation of uroporphyrin. We also demonstrated that in ALA-supplemented cultures, these same compounds lead to accumulation of a large amount of uroporphyrin III, whereas with other PCBs, which were weak inducers of porphyrin synthesis, the accumulated porphyrin was mostly protoporphyrin. was mostly protoporphyrin. Kinetic studies of the sequential decarboxylation of uroporphyrinogen with purified uroporphyrinogen decarboxylase were performed. The 3,4,3',4'-tetrachlorobiphenyl and 3,4,5,3',4',5'-hexachlorobiphenyl strongly inhibit uroporphyrinogen decarboxylase directly at two steps, i.e. first in the formation of hexacarboxylic porphyrinogen III from heptacarboxylic porphyrinogen III and second in the formation of heptacarboxylic porphyrinogen III from uroporphyrinogen III. The results confirmed that porphyrinogenic PCBs primarily inhibit uroporphyrinogen decarboxylase, leading to a depletion of heme as a result of which synthesis of ALA synthetase increased.
D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis; D000818:Animals; D002478:Cells, Cultured; D002645:Chickens; D004790:Enzyme Induction; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011164:Porphyrias / Q000139:chemically induced; D011166:Porphyrins / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014575:Uroporphyrinogen Decarboxylase / Q000037:antagonists & inhibitors
D011166:Porphyrins; D011078:Polychlorinated Biphenyls; D000624:5-Aminolevulinate Synthetase; D014575:Uroporphyrinogen Decarboxylase