Inhibition of rat testicular nuclear kinesins (krp2; KIFC5A) by acrylamide as a basis for establishing a genotoxicity threshold.
Acrylamide is a toxic substance that induces a variety of cellular responses including neurotoxicity, male reproductive toxicity, tumorigenicity, clastogenicity, and DNA alkylation. Evidence is provided that inhibition of the microtubule motor protein kinesin is responsible for acrylamide-induced clastogenicity and aneuploidy. Two kinesin motors, KIFC5A and KRP2, which are responsible for spindle assembly and disassembly of kinetochore MT, respectively, are inhibited by acrylamide. The inhibitory concentration for a response is below the levels shown to adversely affect the cytogenetic parameters. The relative contribution of these inhibitions compared to DNA alkylation is considered. The implications of inhibition of these kinesins as the site of action of acrylamide with regard to risk assessment are substantial as this event will have a threshold and a safe level of acrylamide can be determined.
Friedman
Marvin A
MA
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA. killrat@bellsouth.net
Zeiger
Errol
E
Marroni
Dennis E
DE
Sickles
Dale W
DW
D020106:Acrylamide / Q000008:administration & dosage / Q000494:pharmacology*; D000478:Alkylation; D000818:Animals; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts / Q000032:analysis; D004249:DNA Damage / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D009153:Mutagens / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D018570:Risk Assessment; D013737:Testis / Q000201:enzymology*
D018736:DNA Adducts; D004791:Enzyme Inhibitors; C100588:Kif2c protein, rat; D009153:Mutagens; D020106:Acrylamide; D004247:DNA; D016547:Kinesins