Benzo[a]pyrene Induces Apoptosis in RL95-2 Human Endometrial Cancer Cells by Cytochrome P450 1A1 Activation

Abstract

Benzo[a]pyrene (B[a]P) has been shown to be an inducer of apoptosis in some cell types. To date, due to the lack of an appropriate model system, studies of the cellular and biochemical mechanism(s) by which B[a]P induces apoptosis have been focused on Hepa1c1c7 cells. Moreover, the precise relationship between the bioactivation of B[a]P by CYP1A1 or CYP1B1 and the occurrence of cytotoxicity-mediated apoptosis requires further elucidation. In the present study, we showed that B[a]P-induced apoptosis in RL95-2 cells is accompanied by the activation of caspases. In addition, the mitochondrial changes, including the decrease of mitochondrial potential and the release of mitochondrial cytochrome c and second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein binding protein with low PI (Smac/DIABLO) into the cytosol, support the suggestion that the mitochondrial pathway is robustly associated with B[a]P-evoked apoptosis. This study showed the involvement of the nuclear translocation of mitochondrial apoptosis-inducing factor in B[a]P-induced apoptosis of RL95-2 cells. Exposure to B[a]P up-regulates aryl hydrocarbon receptor, heat-shock protein 90, cytochrome P450 1A1 (CYP1A1), cytochrome P450 1B1 (CYP1B1), and epoxide hydrolase significantly, which might be prerequisites for the conversion of B[a]P to B[a]P-7,8-dihydroxy-9,10-epoxide. Although both CYP1A1 and CYP1B1 proteins were up-regulated significantly by B[a]P, only CYP1A1 exhibited activity. Thus, CYP1A1 is believed to be a central oxidative enzyme that is ultimately required for formation of B[a]P-7,8-dihydroxy-9,10-epoxide from B[a]P in RL95-2 cells. Altogether, our data showed that RL95-2 cells are susceptible to apoptosis by exposure to B[a]P and that B[a]P-evoked apoptosis is mediated predominantly by the activation of CYP1A1. Here we suggest that RL95-2 cells are an excellent model for the investigation of xenobiotic mechanisms associated with CYP1A1 as well as CYP1B1.

Monocrotophos Induced Apoptosis in PC12 Cells: Role of Xenobiotic Metabolizing Cytochrome P450s

“…But, we are hypothesizing the involvement of CYPs in the activation of caspases as another possible route to trigger the apoptosis signalling in PC12 cells receiving MCP exposure. Since, CYPs-mediated apoptotic changes have already been reported in E47 cells [49], and Hepa1c1c7 cells [24], [50] exposed to buthionine sulfoximine and Benzo[a] pyrene respectively. Based on the findings, we propose a schematic flow diagram showing the involvement of selected CYPs in the triggering of ROM induced oxidative stress and apoptosis cascade in PC12 cells exposed to MCP.…”

“…However, the knowledge on specific pathway(s) involved for individual OP-induced toxicity is needed to be elaborating completely. The involvement of different CYPs has been suggested in the process of oxidative stress [12], mutagenicity [13], apoptosis [14], [15], and behavioural deficits [16]. Significant induction in the expression of different CYPs has been reported in liver exposed to structurally unrelated chemicals [16].…”

Benzo[a]pyrene-induced necrosis in the HepG2 cells via PARP-1 activation and NAD+ depletion

“…As a potent carcinogenic agent, BaP has been reported to induce cell death in many cell models (Banerjee et al, 2005;Chung et al, 2007;Kim et al, 2007), most of which are cancer cell lines. This dual nature of BaP in inducing both carcinogenesis and cytotoxicity is of great interest.…”

Analysis of adenosine phosphates in HepG-2 cell by a HPLC–ESI-MS system with porous graphitic carbon as stationary phase

“…Recent studies have suggested the links between benzo[a]pyrene toxicity with cancer and cell death. Benzo[a]pyrene can cause cell death via either apoptosis [25] or necrosis [26], which are two different modes of cell death following exposure to the toxicant. The occurrence of the different modes of cell death depends on energy level.…”