Amino acid and protein targets of 1,2-diacetylbenzene, a potent aromatic gamma-diketone that induces proximal neurofilamentous axonopathy.
The gamma-diketone analogs 1,2-diacetylbenzene (1,2-DAB) and 2,5-hexanedione (2,5-HD), but not the delta-diketone 1,3-diacetylbenzene (1,3-DAB) or the beta-diketone 2,4-hexanedione, induce neuropathological changes in the rodent central and peripheral nervous systems. The molecular targets of these neurotoxic aromatic and aliphatic gamma-diketones, and of their nonneurotoxic structural analogs and ninhydrin, are examined by assessing their differential reactivity with neural and nonneural amino acids and proteins in vitro and in vivo. Whereas 1,2-DAB is chromogenic and forms polymers with amino acids (notably lysine) and proteins (especially lysine-rich proteins), 1,3-DAB lacks these properties. Ninhydrin forms a chromophore without evidence of protein polymerization. 1,2-DAB preferentially targets neurofilament over microtubule protein in vitro and in situ. Based on protein reactivity, 1,2-DAB is three orders of magnitude more reactive than 2,5-HD. Lysine-rich neurofilament protein subunits NF-H and NF-M are more susceptible than lysine-poor NF-L and beta-tubulin to 1,2-DAB. These observations correlate with the development of proximal (1,2-DAB) and distal (2,5-HD) neurofilament-filled axonal swellings and segregated intact microtubules observed during systemic treatment with aromatic and aliphatic gamma-diketones.
Kim
Min-Sun
MS
Center for Research on Occupational Environmental Toxicology, Portland, Oregon 97201, USA.
Hashemi
Seyed B
SB
Spencer
Peter S
PS
Sabri
Mohammad I
MI
D000098:Acetophenones / Q000633:toxicity*; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000187:drug effects*; D002863:Chromogenic Compounds / Q000494:pharmacology*; D004347:Drug Interactions; D007202:Indicators and Reagents / Q000494:pharmacology; D007536:Isomerism; D008297:Male; D016900:Neurofilament Proteins / Q000187:drug effects*; D020258:Neurotoxicity Syndromes / Q000209:etiology; D009555:Ninhydrin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000098:Acetophenones; D000596:Amino Acids; D002863:Chromogenic Compounds; D007202:Indicators and Reagents; D016900:Neurofilament Proteins; C048792:1,2-diacetylbenzene; D009555:Ninhydrin