title: 1,2-diacetylbenzene, the neurotoxic metabolite of a chromogenic aromatic solvent, induces proximal axonopathy.
abstract: Several widely used aromatic hydrocarbon solvents reportedly induce blue-green discoloration of tissues and urine in animals and humans. The chomophore has been proposed to result from a ninhydrin-like reaction with amino groups in proteins. The present study examines the neurotoxic property of 1,2-diacetylbenzene (1,2-DAB), the active metabolite of the chromogenic and neurotoxic aromatic solvent 1,2-diethylbenzene. Rats treated with 1,2-DAB, but not with the nonchromogenic isomer 1,3-DAB or with ninhydrin developed blue discoloration of internal organs, including the brain and spinal cord. Only 1,2-DAB induced limb weakness associated with nerve fiber changes, which were most prominent in spinal cord and spinal roots. Changes began with the formation of proximal, neurofilament-filled axonal swellings of the type seen after treatment with 3,4-dimethyl-2,5-hexanedione, a potent derivative of the active metabolite of the neurotoxic aliphatic hydrocarbon solvents n-hexane and methyl n-butyl ketone. These compounds are metabolized to a gamma-diketone that forms pyrroles with target proteins, such as neurofilament proteins. A comparable mechanism is considered for 1,2-DAB, an aromatic gamma-diketone.
authors.affiliation: Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon 97201, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Kim
authors.forename: M I
authors.initials: MI
authors.lastname: Sabri
authors.forename: V H
authors.initials: VH
authors.lastname: Miller
authors.forename: R J
authors.initials: RJ
authors.lastname: Kayton
authors.forename: D A
authors.initials: DA
authors.lastname: Dixon
authors.forename: P S
authors.initials: PS
authors.lastname: Spencer
mesh_terms: D000098:Acetophenones / Q000633:toxicity*; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D001555:Benzene Derivatives / Q000633:toxicity; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002863:Chromogenic Compounds / Q000633:toxicity*; D007202:Indicators and Reagents / Q000494:pharmacology; D008297:Male; D008854:Microscopy, Electron; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology; D009555:Ninhydrin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D000098:Acetophenones; D001555:Benzene Derivatives; D002863:Chromogenic Compounds; D007202:Indicators and Reagents; C064750:1,2-diethylbenzene; C048792:1,2-diacetylbenzene; D009555:Ninhydrin