title: Effect of hydroxy substituent position on 1,4-naphthoquinone toxicity to rat hepatocytes.
abstract: The effect of hydroxy substitution on 1,4-naphthoquinone toxicity to cultured rat hepatocytes was studied. Toxicity of the quinones decreased in the series 5,8-dihydroxy-1,4-naphthoquinone greater than 5-hydroxy-1,4-naphthoquinone greater than 1,4-naphthoquinone greater than 2-hydroxy-1,4-naphthoquinone, and intracellular GSSG formation decreased in the order 5,8-dihydroxy-1,4-naphthoquinone greater than 5-hydroxy-1,4-naphthoquinone much greater than 1,4-naphthoquinone much greater than 2-hydroxy-1,4-naphthoquinone. The electrophilicity of the quinones decreased in the order 1,4-naphthoquinone much greater than 5-hydroxy-1,4-naphthoquinone greater than 5,8-dihydroxy-1,4-naphthoquinone much greater than 2-hydroxy-1,4-naphthoquinone. Treatment of the hepatocytes with BSO (buthionine sulfoximine) or BCNU (1,3-bis-2-chloroethyl-1-nitrosourea) increased 5-hydroxy-1, 4-naphthoquinone and 5,8-dihydroxy-1,4-naphthoquinone toxicity, whereas neither BSO nor BCNU largely affected 1,4-naphthoquinone and 2-hydroxy-1, 4-naphthoquinone toxicity. Dicumarol increased the toxicity of 1,4-naphthoquinone dramatically and somewhat the toxicity of 2-hydroxy-1,4- naphthoquinone, whereas 5-hydroxy-1,4-naphthoquinone and 5,8-dihydroxy-1,4-naphthoquinone toxicity increased only slightly. The toxicity of 5,8-dihydroxy-1,4-naphthoquinone decreased dramatically in reduced O2 concentration, whereas 1,4-naphthoquinone, 5-hydroxy-1,4-naphthoquinone, and 2-hydroxy-1,4-naphthoquinone toxicity was not largely affected. It was concluded that 5,8-dihydroxy-1,4-naphthoquinone toxicity is due to free radical formation, whereas the toxicity of 1,4-naphthoquinone and of 5-hydroxy-1,4-naphthoquinone also has an electrophilic addition component. The toxicity of 2-hydroxy-1,4-naphthoquinone could not be fully explained by either of these phenomena.
authors.affiliation: Department of Pathology, University of Linköping, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Ollinger
authors.forename: A
authors.initials: A
authors.lastname: Brunmark
mesh_terms: D000818:Animals; D019328:Buthionine Sulfoximine; D002330:Carmustine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D001728:Dicumarol / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D015394:Molecular Structure; D009285:Naphthoquinones / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
chemical_list: D009285:Naphthoquinones; D008717:Methionine Sulfoximine; C005503:naphthazarin; D019328:Buthionine Sulfoximine; D001728:Dicumarol; D005978:Glutathione; C035342:1,4-naphthoquinone; C005090:lawsone; D002330:Carmustine; C005134:juglone