title: Kinetics of ethylene and ethylene oxide in subcellular fractions of lungs and livers of male B6C3F1 mice and male fischer 344 rats and of human livers.
abstract: Ethylene (ET) is metabolized in mammals to the carcinogenic ethylene oxide (EO). Although both gases are of high industrial relevance, only limited data exist on the toxicokinetics of ET in mice and of EO in humans. Metabolism of ET is related to cytochrome P450-dependent mono-oxygenase (CYP) and of EO to epoxide hydrolase (EH) and glutathione S-transferase (GST). Kinetics of ET metabolism to EO and of elimination of EO were investigated in headspace vessels containing incubations of subcellular fractions of mouse, rat, or human liver or of mouse or rat lung. CYP-associated metabolism of ET and GST-related metabolism of EO were found in microsomes and cytosol, respectively, of each species. EH-related metabolism of EO was not detectable in hepatic microsomes of rats and mice but obeyed saturation kinetics in hepatic microsomes of humans. In ET-exposed liver microsomes, metabolism of ET to EO followed Michaelis-Menten-like kinetics. Mean values of V(max) [nmol/(min·mg protein)] and of the apparent Michaelis constant (K(m) [mmol/l ET in microsomal suspension]) were 0.567 and 0.0093 (mouse), 0.401 and 0.031 (rat), and 0.219 and 0.013 (human). In lung microsomes, V(max) values were 0.073 (mouse) and 0.055 (rat). During ET exposure, the rate of EO production decreased rapidly. By modeling a suicide inhibition mechanism, rate constants for CYP-mediated catalysis and CYP inactivation were estimated. In liver cytosol, mean GST activities to EO expressed as V(max)/K(m) [μl/(min·mg protein)] were 27.90 (mouse), 5.30 (rat), and 1.14 (human). The parameters are most relevant for reducing uncertainties in the risk assessment of ET and EO.
authors.affiliation: Institute of Toxicology, German Research Center for Environmental Health, Helmholtz Zentrum München, D-85764 Neuherberg, Germany.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: György András
authors.initials: GA
authors.lastname: Csanády
authors.forename: Winfried
authors.initials: W
authors.lastname: Kessler
authors.forename: Dominik
authors.initials: D
authors.lastname: Klein
authors.forename: Helmut
authors.initials: H
authors.lastname: Pankratz
authors.forename: Christian
authors.initials: C
authors.lastname: Pütz
authors.forename: Nadine
authors.initials: N
authors.lastname: Richter
authors.forename: Johannes Georg
authors.initials: JG
authors.lastname: Filser
mesh_terms: D000818:Animals; D002849:Chromatography, Gas; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004785:Environmental Pollutants / Q000493:pharmacokinetics*; D004851:Epoxide Hydrolases / Q000378:metabolism; D005027:Ethylene Oxide / Q000493:pharmacokinetics*; D005030:Ethylenes / Q000493:pharmacokinetics*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity
chemical_list: D004785:Environmental Pollutants; D005030:Ethylenes; D003577:Cytochrome P-450 Enzyme System; C036216:ethylene; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases; D005027:Ethylene Oxide