Comparative metabolism and disposition of ethoxyquin in rat and mouse. II. Metabolism

Abstract

1. The major pathways of ethoxyquin (EQ) metabolism in both the rat and mouse are O-deethylation and conjugation to endogenous substrates. 2. The two major EQ-derived metabolites excreted in rat urine were in the form of sulphate conjugates, 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline sulphate, and 1,2,3,4-tetrahydro-3,6-dihydroxy-4-methylene-2,2-dimethylquinoline sulphate. The latter apparently arises from an intramolecular rearrangement of the 3,4-epoxide of ethoxyquin. 3. Mouse urine contained one major glucuronide, 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline glucuronide as well as one major sulphate conjugate, 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline sulphate. 4. EQ-derived radioactivity was excreted in rat bile, mainly as GSH conjugates, with little unchanged EQ present. Two of the biliary metabolites are glutathione conjugates of ethoxyquin 3,4-epoxide; the third appears to be a conjugate of either ethoxyquin 7,8-epoxide or 2,2,4-trimethylquinol-6-one.

Disruption of estrogen homeostasis as a mechanism for uterine toxicity in Wistar Han rats treated with tetrabromobisphenol A

“…Sulfotransferase activity was not measured. In rodents, saturation of sulfotransferases (SULTs) generally precedes that of UGTs (Burka et al, 1996; Hjelle and Klaassen, 1984); therefore, it can be assumed that the conjugation capacity for endogenous estrogen was compromised in the NTP study. In the present study, the gene responses for the assayed UGT and SULT isoforms were variable in tissues; however, the data indicated potential for change in the ratio of sulfation to glucuronidation after five days of treatment with 250 mg TBBPA/kg.…”

Investigations on the Metabolism and Potentially Adverse Effects of Ethoxyquin Dimer, a Major Metabolite of the Synthetic Antioxidant Ethoxyquin in Salmon Muscle

“…EQDM administration reduced liver Cyp1a1 mRNA concentrations to less than 3% that of control rats, and Cyp2b1 mRNA was increased to 192% that of control rats. Inhibition of rat CYP activity by EQ has been reported (11,28,32), and Parke et al (42) suggested that EQ binds to CYP enzymes and thereby inhibits their activity, manifested as increased effects of the sedative hexobarbitone after a single dose of EQ. However, repeated doses of EQ produced the opposite effect, indicating an adaptive response through the induction of CYP enzymes.…”

“…In the present study, Ugt1a mRNA transcription and overall UGT activity were not different in EQDM and control rats, apparently indicating that glucoronidation is not a prevalent pathway for metabolism of EQDM. In addition to glucoronidation, large amounts of glutathione conjugates were observed in bile of rats exposed to EQ, implying that GST is involved in EQ metabolism (11).…”

“…UGT-mediated and sulfotransferase-mediated conjugation seem to be the major phase II pathways of EQ metabolism in rats and mice (11). However, although Sanders et al (48) reported the same disposition of EQ in mouse and rat, the metabolic pathways differed significantly; glucoronidation was a more prevalent pathway in mouse than in rat, and in rats more than 50% of the EQ derivatives were present as sulfate conjugates (11). In the present study, Ugt1a mRNA transcription and overall UGT activity were not different in EQDM and control rats, apparently indicating that glucoronidation is not a prevalent pathway for metabolism of EQDM.…”

“…Glucuronidation and conjugation by UGT and GST are major pathways for the inactivation and elimination of endogenous compounds but also are significant for other lipophilic compounds such as certain xenobiotics (29). The mechanisms of EQ hepatic biotransformation at the chemical and biochemical levels have been partially elucidated by Burka et al (11), who suggested three different CYP isozyme-mediated steps in phase I metabolism of EQ: O-dealkylation, aromatic ring hydroxylation, and epoxidation.…”