Cellular glutathione conjugation of aziridines in isolated rat hepatocytes.
Glutathione conjugation of aziridines was found in isolated rat hepatocytes in experiments using the optical isomers of (1- and d-) aziridinecarboxylic acid (AZC) and (1- and d-) 1-methyl-2-beta-naphthylaziridine (NAZ). 1-AZC much more effectively consumed glutathione than d-AZC, and the yield of the glutathione conjugate during 2 hr of incubation exceeded 200% of the cellular glutathione detected at the initiation of the incubation. Such a high yield of 1-AZC-GSH conjugate would occur only when conjugation efficiently proceeds without interference against the GSH resynthesis route in the liver cells. The cytotoxicity of 1-AZC was very weak and did not affect cell viability of the isolated hepatocytes even after the formation of AZC-GSH conjugate. Consequently, we supposed that GSH is not essential for supporting the viability of the isolated hepatocytes. For very slow GSH conjugate formation of d-AZC, we envisaged poor membrane transport of the d-isomer resembling to the selective incorporation of d- and 1-proline observed in some plant cells. Both isomers of NAZ were markedly cytotoxic and depressed the cell viability. The yield of the glutathione conjugate from NAZ did not exceed the cellular GSH level detected at the initial stage of incubation. The highly cytotoxic compound nitrosomethane, generated in the first biotransformation step of the metabolism of NAZ, can obstruct the resynthesis route of GSH by inhibiting the ATP generation process as discussed previously (Ref. 3). Decreasing the cellular GSH by treatment with 1-AZC enhanced the susceptibility of the isolated hepatocytes to NAZ toxicity. d-AZC did not affect the viability of cells treated with NAZ.
Hata
Y
Y
Shionogi Research Laboratories, Shionogi & Co. Ltd., Osaka, Japan.
Watanabe
M
M
Tonda
K
K
Hirata
M
M
D000818:Animals; D001388:Aziridines / Q000378:metabolism* / Q000494:pharmacology; D001389:Azirines / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D001388:Aziridines; D001389:Azirines; D005978:Glutathione