Abstract
The excretion and metabolism of neurotoxic 1,2-diethylbenzene (1,2-DEB) was studied in male Sprague-Dawley rats after i.v. (1 mg/kg) or oral (1 or 100 mg/kg) administration of 1,2-diethyl[U-14C]benzene ([14C]1,2-DEB). Whatever the treatment, radioactivity was mainly excreted in urine (65–76% of the dose) and to a lower extent in feces (15–23% of the dose), or via exhaled air (3–5% of the dose). However, experiments with rats fitted with a biliary cannula demonstrated that about 52 to 64% of the administered doses (1 or 100 mg/kg) were initially excreted in bile. Biliary metabolites were extensively reabsorbed from the gut and ultimately excreted in urine after several enterohepatic circulations. Insignificant amounts of unchanged 1,2-DEB were recovered in the different excreta (urine, bile, and feces). As reported previously, presence of 1-(2′-ethylphenyl)ethanol (EPE) was confirmed in urine and demonstrated in bile and feces. The two main [14C]1,2-DEB metabolites accounted for 57 to 79% of urinary and biliary radioactivity, respectively. β-Glucuronidase hydrolysis and electron impact mass spectra results strongly supported their glucuronide structure. Additionally, these two main metabolites were thought to be the glucuronide conjugates of the two potential enantiomers of EPE. The results indicate that the main initial conversion step of the primary metabolic pathway of 1,2-DEB appears to be the hydroxylation of the α-carbon atom of the side chain. The presence of two glucuronide conjugates of EPE in the urine in a ratio different from one suggests that the metabolic conversion of 1,2-DEB is under stereochemical control.
Footnotes
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Send reprint requests to: Dr. Jean-Paul Payan, Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France. E-mail: payanjp{at}inrs.fr
- Abbreviations used are::
- DEB
- diethylbenzene
- 1,2-DAB
- 1,2-diacetylbenzene
- 1,2-DEB
- 1,2-diethylbenzene
- [14C]1,2-DEB
- 1,2-diethyl[U-14C]benzene
- EI
- electron impact
- EPE
- 1-(2′-ethylphenyl)ethanol
- Et2O
- diethyl ether
- FAB
- fast atom bombardment
- GA1 and GA2
- glucuronide conjugates of EPE
- GC/MS
- gas chromatography/mass spectrometry
- MS
- mass spectrometry
- [14C]HCBD
- [14C]hexachlorobutadiene
- PICI
- positive ion chemical ionization
- Received May 10, 1999.
- Accepted August 11, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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