URINARY METABOLITE PROFILE OF PHENYL AND O-CRESYL GLYCIDYL ETHER IN RATS - IDENTIFICATION OF A NOVEL PATHWAY LEADING TO N-ACETYLSERINE O-CONJUGATES

The urinary excretion of metabolites of phenyl glycidyl ether (PGE) an d o-cresyl glycidyl ether (o-CGE) was investigated in rats. Urine was collected, in fractions, from rats intraperitoneally administered PGE or o-CGE in doses ranging from 0.033 to 1.0 mmol/kg. The metabolites w ere extracted from acidified urine with ethyl acetate or diethyl ether , and their identity was elucidated by GC/MS analysis. The epoxide of PGE can be inactivated by glutathione (GSH) conjugation or epoxide hyd rolysis. After further metabolism, these routes lead to the urinary ex cretion of phenyl glycidyl ether mercapturic acid (PGEMA) and 3-(pheny loxy)lactic acid (POLA). The excretion of PGEMA and POLA was described before and is confirmed in this study. Additionally, a new metabolite was identified as N-acetyl-O-phenylserine (NAPS), which is proposed t o be formed from POLA by subsequent oxidation, transamination, and N-a cetylation. For PGEMA a linear dose-excretion relationship was found ( r(2) = 0.988), and the percentage of the dose excreted declined from 2 7 % to 10 % with increasing PGE dose. For NAPS also a linear dose-excr etion relationship was found (r(2) = 0.985), and NAPS accounted for 27 % of the PGE dose. The excretion of PGEMA and NAPS was rather fast: 9 3 % and 75 %, respectively, of the respective total cumulative amounts excreted was already collected within 6 h after administration. The u rinary metabolite profile of o-CGE was not investigated in rats before . Three urinary metabolites of o-CGE were identified, namely, 3-(o-cre syloxy)lactic acid (COLA), o-cresyl glycidyl ether mercapturic acid (o -CGEMA), and N-acetyl-O-(o-cresyl)serine (NAGS), showing that the meta bolite profiles of PGE and o-CGE are comparable. Up to a o-CGE dose of 0.333 mmol/kg, the excretion of o-CGEMA was linear (r(2) = 0.997), wh ile above this dose the excretion did not increase anymore. The percen tage of the o-CGE dose excreted as o-CGEMA declined from 31 % to 11 % with increasing dose. Again 93 % of the total cumulative amount of o-C GEMA excreted was collected within 6 h after administration of o-CGE. Analytical methods were developed for the quantitative determination o f mercapturic acid metabolites of PGE and o-CGE. These methods were su fficiently sensitive for their determination in urine of rats administ ered PGE or o-CGE in the dose range applied. It is anticipated that th e analytical methods developed are also sufficiently sensitive to inve stigate excretion of the mercapturic acid metabolites in humans occupa tionally exposed to low air concentrations (< 6 mg/m(3) of air, 8h-TWA ) of PGE or o-CGE.