PK-11195 AGGRAVATES 3,5-DIETHOXYCARBONYL-1,4-DIHYDROCOLLIDINE-INDUCEDHEPATIC PORPHYRIA IN RATS

There is evidence to suggest that peripheral-type benzodiazepine recep tors (PER) are involved in porphyrin transport during erythroid differ entiation, and it is possible that these receptors have an important r ole in heme biosynthesis, We examined the biochemical and ultrastructu ral alterations in rat liver following experimentally induced acute he patic porphyria, as well as the effects of the administration of a sel ective PER Ligand, PK 11195. The most severe pathological conditions w ere found in rats that received a combined treatment of the porphyrino genic agent 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and PK 111 95, Transmission electron microscopy showed a correlation between the ultrastructural pathology of the liver, the total porphyrin levels in urine and Liver, and the porphobilinogen levels in urine, Hepatocytes in this acute porphyria showed the development of large secondary lyso somes containing crystalline aggregates of protoporphyrin. Bile canali culi were grossly enlarged, contained aggregates of protoporphyrin cry stals, and showed the presence of bile thrombi, In addition, prominent bundles of collagen fibers (fibrosis) were commonly found in livers o f rats that had been treated with DDC or DDC and PK 11195, We conclude that the administration of PK 11195 to porphyric rats aggravates porp hyrin accumulation and cellular damage in the Liver, Perhaps this evid ence suggests that PK 11195 blocks the binding of protoporphyrin IX to PER, thus elevating the content of protoporphyrin IX in Liver.