- 作者: MontserratMari DefengWu Natalia Nieto Arthurl. Cederbaum
- 作者服務機構: Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, N.Y., USA
- 中文摘要: --
- 英文摘要: Induction of cytochrome P450 2E1 (CYP2E 1) by ethanolappears to be one of the central pathways by which etha-nol generates a state of oxidative stress. Glutathione(GSH) is critical in preserving the proper cellular redoxbalance and for its role as a cellular protectant. The goalof the present study was to characterize the GSH homeo-stasis in human hepatocarcinoma cells (HepG2-E47cells) that overexpress CYP2E1. Toxicity in the E47 cellswas markedly enhanced after GSH depletion by buthion-ine sulfoximine (BSO) treatment. The antioxidant troloxpartially prevented the apoptosis and necrosis, whilediallylsulfide, a CYP2E1 inhibitor, was fully protective.Damage to mitochondria appears to play a role in theCYP2E1- and BSO-dependent toxicity. CYP2E1-overex-pressing cells showed increases in total GSH levels, GSHsynthetic rate and in -glutamylcysteine synthetase(GCS) mRNA. This GCS increase was due to transcrip-tional activation of the GCS gene and could be blockedby certain antioxidants. Activity, protein and mRNA lev-els for other antioxidants such as catalase, α- and micro-somal glutathione transferases were also increased inthe E47 cells. Up-regulation of these antioxidant genesmay reflect an adaptive mechanism to remove CYP2E1-derived oxidants. These oxidants are diffusable andwere able to elevate collagen type I protein in a co-cul-ture system consisting of the E47 cells + rat hepatic stel-late cells. Such interactions between CYP2E1, mitochon-dria and altered GSH homeostasis, and elevation of col-lagen levels, may play a role in alcohol-induced liverinjury.
- 中文關鍵字: --
- 英文關鍵字: CYp2E1. Glutathione. Antioxidants. Toxicity. HepG2 cells. Stellate cells. Collagen type l