In vivo and in vitro formation of glutathione conjugates from the K-region epoxides of 1-nitropyrene.
4,5-Epoxy-4,5-dihydro-1-nitropyrene (1-nitropyrene 4,5-oxide) and 9,10-epoxy-9,10-dihydro-1-nitropyrene (1-nitropyrene 9,10-oxide), which are electrophilic metabolites formed during the metabolism of the environmental pollutant, 1-nitropyrene, reacted slowly with glutathione. The rate of conjugation was greatly enhanced by the addition of purified rat liver glutathione (GSH) transferases, with transferases 3-3 and 4-4 exhibiting higher catalytic activities than transferases 1-1, 2-2 and 7-7. Two GSH conjugates were formed from each of the oxides: 1-nitropyrene 4,5-oxide gave a 1:1 mixture of 4-(glutathion-S-yl)-5-hydroxy-4,5-dihydro-1-nitropyrene and 5-(glutathion-S-yl)-4-hydroxy-4,5-dihydro-1-nitropyrene while 1-nitropyrene 9,10-oxide gave a 2:1 mixture of 9-(glutathion-S-yl)-10-hydroxy-9,10-dihydro-1-nitropyrene and 10-(glutathion-S-yl)-9-hydroxy-9,10-dihydro-1-nitropyrene. Both K-region oxides were converted to trans-dihydrodiols by hepatic microsomal epoxide hydrase, and faster rates were observed with 1-nitropyrene 4,5-oxide. In subsequent experiments [4,5,9,10-3H]1-nitropyrene was administered to Sprague-Dawley rats by intravenous and intraperitoneal injections. HPLC analysis of biliary metabolites indicated the presence of four GSH conjugates that were identical to those obtained from reactions of the K-region oxides with GSH. In addition, glucuronide conjugates were detected from trans-4,5-dihydroxy-4,5-dihydro-1-nitropyrene (1-nitropyrene trans-4,5-dihydrodiol) but not trans-9,10-dihydroxy-9,10-dihydro-1-nitropyrene (1-nitropyrene trans-9,10-dihydrodiol). These data combined with earlier studies indicate that 1-nitropyrene is oxidized preferentially to 1-nitropyrene 4,5-oxide and that, while the main detoxification pathway of 1-nitropyrene 9,10-oxide is GSH conjugation, 1-nitropyrene 4,5-oxide is excreted via both GSH conjugation and dihydrodiol formation followed by O-glucuronidation.
Djurić
Z
Z
National Center for Toxicological Research, Jefferson, AR 72079.
Coles
B
B
Fifer
E K
EK
Ketterer
B
B
Beland
F A
FA
D000818:Animals; D001646:Bile / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D004852:Epoxy Compounds / Q000378:metabolism*; D004988:Ethers, Cyclic / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011721:Pyrenes / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D011721:Pyrenes; D005982:Glutathione Transferase; D005978:Glutathione; C032668:1-nitropyrene