PK 11195 aggravates 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced hepatic porphyria in rats.
There is evidence to suggest that peripheral-type benzodiazepine receptors (PBR) are involved in porphyrin transport during erythroid differentiation, and it is possible that these receptors have an important role in heme biosynthesis. We examined the biochemical and ultrastructural alterations in rat liver following experimentally induced acute hepatic porphyria, as well as the effects of the administration of a selective PBR ligand, PK 11195. The most severe pathological conditions were found in rats that received a combined treatment of the porphyrinogenic agent 3,5-diethoxycarbonyl-1,4- dihydrocollidine (DDC) and PK 11195. 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 lysosomes containing crystalline aggregates of protoporphyrin. Bile canaliculi were grossly enlarged, contained aggregates of protoporphyrin crystals, and showed the presence of bile thrombi. In addition, prominent bundles of collagen fibers (fibrosis) were commonly found in livers of rats that had been treated with DDC or DDC and PK 11195. We conclude that the administration of PK 11195 to porphyric rats aggravates porphyrin accumulation and cellular damage in the liver. Perhaps this evidence suggests that PK 11195 blocks the binding of protoporphyrin IX to PBR, thus elevating the content of protoporphyrin IX in liver.
Fonia
O
O
Department of Pharmacology, Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa.
Weizman
R
R
Coleman
R
R
Kaganovskaya
E
E
Gavish
M
M
D000818:Animals; D001648:Bile Canaliculi / Q000187:drug effects / Q000648:ultrastructure; D003997:Dicarbethoxydihydrocollidine; D005355:Fibrosis; D007546:Isoquinolines / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D017094:Porphyrias, Hepatic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D011166:Porphyrins / Q000378:metabolism / Q000652:urine; D051381:Rats; D017208:Rats, Wistar
D007546:Isoquinolines; D011166:Porphyrins; D003997:Dicarbethoxydihydrocollidine; C037850:PK 11195