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Titolo:
Identification of novel metabolites of butadiene monoepoxide in rats and mice
Autore:
Richardson, KA; Peters, MMCG; Megens, RHJJJ; van Elburg, PA; Golding, BT; Boogaard, PJ; Watson, WP; van Sittert, NJ;
Indirizzi:
Shell,Int Chem, Shell Res & Technol Ctr, Dept Toxicol, NL-1030 BN Amsterdam Shell Int Chem Amsterdam Netherlands NL-1030 BN ol, NL-1030 BN Amsterdam Univar,wcastle Upon Tyne, Dept Chem, Newcastle Upon Tyne NE1 7RU, Tyne & We Univ Newcastle Upon Tyne Newcastle Upon Tyne Tyne & Wear England NE1 7RU
Titolo Testata:
CHEMICAL RESEARCH IN TOXICOLOGY
fascicolo: 12, volume: 11, anno: 1998,
pagine: 1543 - 1555
SICI:
0893-228X(199812)11:12<1543:IONMOB>2.0.ZU;2-P
Fonte:
ISI
Lingua:
ENG
Soggetto:
SPRAGUE-DAWLEY RATS; LEVEL INHALATION EXPOSURE; LIVER-MICROSOMES; SPECIES-DIFFERENCES; 1,3-BUTADIENE; MONOXIDE; TOXICITY; QUANTITATION; MECHANISMS; ACROLEIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
49
Recensione:
Indirizzi per estratti:
Indirizzo: Watson, WP ShellNInt Chem, Shell Res & Technol Ctr, Dept Toxicol, POB 38000, NL-1030 B Shell Int Chem POB 38000 Amsterdam Netherlands NL-1030 BN 30 B
Citazione:
K.A. Richardson et al., "Identification of novel metabolites of butadiene monoepoxide in rats and mice", CHEM RES T, 11(12), 1998, pp. 1543-1555

Abstract

Differences in the metabolism of 1,3-butadiene (Bd) in rats and mice may account for the observed species difference in carcinogenicity. Previous studies of the metabolic fate of Ed have identified epoxide formation as a keymetabolic transformation which gives 1,2-epoxy-3-butene (BMO), although some evidence of aldehyde metabolites is reported. In this study, male Sprague-Dawley rats and male B6C3F1 mice received single doses of [4-C-14]BMO at 1, 5, 20, and 50 mg/kg of body weight (0.014, 0.071, 0.286, and 0.714 mmol/kg of body weight). Analysis of urinary metabolites indicated that both species preferentially metabolize BMO by direct reaction with GSH when given by ip administration. The excretion of (R)-2-(N-acetyl-L-cystein-S-yl)-1-hydroxybut-3-ene (IIa), 1-(N-acetyl-L-cystein-S-yl)-2-(S)-hydroxybut-3-ene (IIb), 1-(N-acetyl-L-cystein-S-yl)-2-(R)-hydroxybut-3-ene (IIc), and (S)-2-(N-acetyl-L-cystein-S-yl)- 1-hydroxybut-3-ene (IId) accounted for 48-64% of urinary radioactivity in rats and 46-54% in mice. The metabolites originatingfrom the R-stereoisomer of BMO (IIc and IId) predominated over those arising from the S-stereoisomer (IIa and IIb) in both species. IIc was formed preferentially in mice and IId in rats. The corresponding mercaptoacetic acids, S-(1-hydroxybut-3-en-2-yl)mercaptoacetic acid (IIf) and S-(2-hydroxybut-3-en-1-yl)mercaptoacetic acid (IIg), were identified only in mouse urine (ca. 20% of the recovered radioactivity,, 4-(N-Acetyl-L-cystein-S-yl)- 1,2-dihydroxybutane (Ia), a metabolite derived from hydrolysis of BMO, accounted for 10-17% of the radioactivity in rat and 6-10% in mouse urine. 4-(N-Acetyl-L-cystein-S-yl)-2-hydroxybutanoic acid (1b), 3-(N-acetyl-L-cystein-S-yl)propan-1-ol (Ic), and 3-(N-acetyl-L-cystein-S-yl)propanoic acid (Id:). also derived from the hydrolysis of RR IO, were only present in the rat. Metabolites of 1,2,3,4-diepoxybutane (DEB) were not detected after administration of BMO in rat or mouse urine. This study showed both quantitative and qualitative differences in the metabolism of BMO with varying doses and between species. The data aid in the safety evaluation of Ed and contribute to the interpretation of mathematical models developed for quantitative risk assessment and extrapolation of animals to humans.

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Documento generato il 30/09/20 alle ore 12:35:19