Mechanism of PCB-induced porphyria and yusho disease

PCBs are known to be potent inducers of chemical porphyria. We studied the structure-activity relationship of synthetic PCBs as porphyrin inducers and found that 3,4,3',4'-tetrachlorobiphenyl, 3,4,3',4',5'-pentachlorobiphenyl, and 3,4,5,3',4',5'-hexachlorobiphenyl were the most active inducers. The structural requirement for potent porphyrinogenic activity of PCB isomers was the substitution of chlorine atoms at the para and meta positions. Isomers fulfilling this requirement had more highly conjugated and nearly coplanar conformations. In addition, it was demonstrated that inhibition of UROD by the most active porphyrin inducers occurred in vitro using purified enzyme. These findings could explain how porphyrinogenic PCBs, by primarily inhibiting UROD and hence depleting heme, ultimately increase ALAS synthesis. The outbreak of yusho disease in Japan (which was caused by PCB-contaminated rice oil) and a similar episode of food poisoning in Taiwan (which was also related to PCB contamination) were discussed, particularly with reference to urinary porphyrin levels and clinical response.