title: Metabolic inactivation of 2-oxiranylmethyl 2-ethyl-2,5-dimethylhexanoate (C10GE) in skin, lung and liver of human, rat and mouse.
abstract: The inactivation of 2-oxiranylmethyl 2-ethyl-2,5-dimethylhexanoate (C10GE), one of the most abundant isomers of the epoxy-resin Carduras E-10 glycidyl ester, was studied in subcellular fractions of human, C3H mouse and F344 rat liver, lung and skin. C10GE is chemically very stable and resistant to aqueous hydrolysis, but it was rapidly metabolized in both cytosolic and microsomal fractions of all organs by epoxide hydrolase (EH)-catalysed hydrolysis of the epoxide moiety as well as carboxylesterase (CE)-catalysed hydrolysis of the ester bond. In cytosol the epoxide group was also efficiently conjugated with glutathione, catalysed by glutathione S-transferase (GST), but this conjugation was much less important than hydrolysis in human as well as rodent samples. Although CE-catalysed hydrolysis of C10GE would theoretically give rise to the formation of glycidol, a directly acting mutagen, it is highly unlikely that any significant level of glycidol would occur in vivo since reported rates of inactivation of glycidol exceed the total rate of hydrolysis of C10GE. The overall rates of inactivation in vitro decreased in the following order: mouse > rat > human. Scaling of the data in vitro to clearances in vivo suggests that the detoxifying capacity in the rodents is similar and about an order of magnitude greater than in human. Nevertheless, the rate of inactivation is 2-3 orders of magnitude greater than for simple epoxides such as butadiene monoxide and about one order of magnitude higher than for the diglycidyl ether of bisphenol A (BADGE). The transdermal penetration and metabolism of [14C]-C10GE was studied in fresh full-thickness mouse, and dermatomized human and rat skin. Of the total radioactivity applied on the skin, only 0.24+/-0.06 (SD), 1.8+/-0.2 and 6.8+/-0.6% penetrated through human, mouse and rat skin respectively. The corresponding apparent skin permeability constants were 0.81, 6.42 and 26.4 x 10(-6) cm/h. During transdermal penetration, [14C]-C10GE was extensively hydrolysed to the corresponding diol and the free acid. Only 0.01, 0.11 and 0.21]% of the applied dose was absorbed unchanged through the human, mouse and rat skin respectively.
authors.affiliation: Department of Molecular Toxicology, Shell Research and Technology Center, Amsterdam, The Netherlands. Peter.J.Boogaard@opc.shell.com
authors.forename: P J
authors.initials: PJ
authors.lastname: Boogaard
authors.forename: P A
authors.initials: PA
authors.lastname: van Elburg
authors.forename: K P
authors.initials: KP
authors.lastname: de Kloe
authors.forename: W P
authors.initials: WP
authors.lastname: Watson
authors.forename: N J
authors.initials: NJ
authors.lastname: van Sittert
mesh_terms: D000328:Adult; D000818:Animals; D003652:Decanoic Acids / Q000493:pharmacokinetics*; D005027:Ethylene Oxide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008658:Inactivation, Metabolic; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008875:Middle Aged; D051381:Rats; D011916:Rats, Inbred F344; D012867:Skin / Q000378:metabolism*
chemical_list: D003652:Decanoic Acids; C043703:tert-decanoic acid oxiranylmethyl ester; D005978:Glutathione; D005027:Ethylene Oxide