title: Haloalkylamine-induced renal papillary necrosis: a histopathological study of structure-activity relationships.
abstract: The haloalkylamine 2-bromoethanamine (BEA) causes necrosis of renal papillae of rats within 24 h of a single intraperitoneal dose greater than or equal to 100 mg/kg. Nine structural analogues of BEA, differing by halide substitution, alkyl chain elongation or amine substitution, were tested for their ability to induce renal papillary lesions in rats. Three compounds (2-chloroethanamine, 3-bromopropanamine and 2-chloro-N,N-dimethylethanamine) induced lesions which were morphologically indistinguishable from those of BEA. All the molecular structural variations investigated reduced papillotoxicity compared with BEA, the parent compound. A variety of non-renal lesions including hepatic, adrenal, testicular and lymphoid necroses were also encountered. The most toxic compound was 2-fluorethanamine, a 5 mg/kg dose of which was lethal and induced renal corticomedullary mineralization and centrilobular hepatic necrosis. One analogue, 3-bromo-2-hydroxypropanamine, caused rapid and extensive necrosis of the adrenal pars fasciculata and reticularis, simulating human Waterhouse Friderichsen syndrome. The three newly identified renal papillotoxins are all theoretically capable of generating direct-acting alkylating species in solution and their activity as direct-acting mutagens in the Ames bacterial mutagenicity test with TA100 (indicating base pair substitution) closely correlated with their potency as papillotoxins. We therefore hypothesize that non-enzymically formed direct-acting alkylating species mediate these papillary lesions, and that the target selectivity of haloalkylamine toxicity most probably results from the accumulation of these alkylating species in papillary tissue.
authors.affiliation: Robens Institute, Guildford, Surrey, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Powell
authors.forename: P
authors.initials: P
authors.lastname: Grasso
authors.forename: C
authors.initials: C
authors.lastname: Ioannides
authors.forename: J
authors.initials: J
authors.lastname: Wilson
authors.forename: J W
authors.initials: JW
authors.lastname: Bridges
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005021:Ethylamines / Q000494:pharmacology / Q000633:toxicity*; D007679:Kidney Medulla / Q000473:pathology; D007681:Kidney Papillary Necrosis / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D009154:Mutation / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
chemical_list: D005021:Ethylamines; C004504:2-bromoethylamine