title: Toxicity assessment of papaverine hydrochloride and papaverine-derived metabolites in primary cultures of rat hepatocytes.
abstract: The present study was undertaken to assess and compare the toxic effects of papaverine hydrochloride and its metabolites. Primary cell cultures of rat hepatocytes were treated with papaverine (papaver), 3'-O-desmethyl (3'-OH), 4'-O-desmethyl (4'-OH), and 6-O-desmethyl (6-OH) papaverine at 1 x 10(-5), 1 x 10(-4), and 1 x 10(-3) M for 4, 8, 12, and 24-h periods. Cell injury was determined by: a) cell viability using the trypan blue exclusion test; b) cytosolic enzyme leakage of lactate dehydrogenase and aspartate aminotransferase; c) morphologic alterations; and d) lactate:pyruvate (L:P) ratios. Cell cultures showed concentration- and time-dependent toxic responses. For example, a decrease in cell viability and an increase in enzyme leakage were observed after cell treatment with 1 x 10(-4) and 1 x 10(-3) M papaver for 8 h; 1 x 10(-3) M 6-OH papaverine for 8 h and 1 x 10(-4) M for 24 h; and 1 x 10(-3) M 4'-OH papaverine for 24 h (P less than 0.05). Furthermore, changes in morphology correlated to cell viability and enzyme release in those cultures treated with papaver, 4'-OH and 6-OH papaverine. Some of these changes included size deformation, cell detachment from the dishes, and cell necrosis. On the other hand, an increase in L:P ratios (P less than 0.05) was detected with papaver as early as 8 h with 1 x 10(-4) and 1 x 10(-3) M and 12 h with 1 x 10(-5) M; 6-OH showed an increase in L:P ratios at 8 h with 1 x 10(-3) M and 12 h with 1 x 10(-4) M; these changes were evident with with 4'-OH at 12 h with 1 x 10(-3) M. In contrast, cells treated with 3'-OH papaverine did not show significant damage with any time period and concentration used in this study. The results of this study indicate that papaverine-derived metabolites are less cytotoxic than its parent compound, papaver. The toxicity was ranked as follows: papaver greater than 6-OH greater than 4'-OH greater than -3'-OH.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin 78712.
authors.forename: J C
authors.initials: JC
authors.lastname: Davila
authors.forename: C G
authors.initials: CG
authors.lastname: Reddy
authors.forename: P J
authors.initials: PJ
authors.lastname: Davis
authors.forename: D
authors.initials: D
authors.lastname: Acosta
mesh_terms: D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010208:Papaverine / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: C064514:3'-hydroxypapaverine; C064513:4'-hydroxypapaverine; C064512:6-hydroxypapaverine; D010208:Papaverine; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases