Effect of Remifentanil on Mitochondrial Oxygen Consumption of Cultured Human Hepatocytes

Abstract

During sepsis, liver dysfunction is common, and failure of mitochondria to effectively couple oxygen consumption with energy production has been described. In addition to sepsis, pharmacological agents used to treat septic patients may contribute to mitochondrial dysfunction. This study addressed the hypothesis that remifentanil interacts with hepatic mitochondrial oxygen consumption. The human hepatoma cell line HepG2 and their isolated mitochondria were exposed to remifentanil, with or without further exposure to tumor necrosis factor-α (TNF-α). Mitochondrial oxygen consumption was measured by high-resolution respirometry, Caspase-3 protein levels by Western blotting, and cytokine levels by ELISA. Inhibitory κBα (IκBα) phosphorylation, measurement of the cellular ATP content and mitochondrial membrane potential in intact cells were analysed using commercial ELISA kits. Maximal cellular respiration increased after one hour of incubation with remifentanil, and phosphorylation of IκBα occurred, denoting stimulation of nuclear factor κB (NF-κB). The effect on cellular respiration was not present at 2, 4, 8 or 16 hours of incubation. Remifentanil increased the isolated mitochondrial respiratory control ratio of complex-I-dependent respiration without interfering with maximal respiration. Preincubation with the opioid receptor antagonist naloxone prevented a remifentanil-induced increase in cellular respiration. Remifentanil at 10× higher concentrations than therapeutic reduced mitochondrial membrane potential and ATP content without uncoupling oxygen consumption and basal respiration levels. TNF-α exposure reduced respiration of complex-I, -II and -IV, an effect which was prevented by prior remifentanil incubation. Furthermore, prior remifentanil incubation prevented TNF-α-induced IL-6 release of HepG2 cells, and attenuated fragmentation of pro-caspase-3 into cleaved active caspase 3 (an early marker of apoptosis). Our data suggest that remifentanil increases cellular respiration of human hepatocytes and prevents TNF-α-induced mitochondrial dysfunction. The results were not explained by uncoupling of mitochondrial respiration.

The role of mitochondria in physical activity and its adaptation on aging

“…According to Djafarzadeh, Vuda, Takala et al (2012), the pathogens associated with mitochondrial dysfunction are multifactorial, but the formation of nitric oxide (NO), the overproduction of ROS, the antioxidant deficiency and the increased permeability of the mitochondrial inner membrane, are the most likely contributions for these activities. Safdar, Bourgeois, Ogborn et al (2011) makes an analogy between the reduction of quality of mitochondria, aging and related diseases such as cancer, diabetes, obesity, dementia, osteoporosis and even neurometabolic syndromes.…”

Experimental immunology Effects of sufentanil on human gastric cancer cell line SGC-7901 in vitro

“…For instance, morphine inhibited tumor cell proliferation at the concentration of less than 10 μM [ 1 ] and exogenous morphine can inhibit the growth of human gastric cancer cell line MGC-803 [ 12 ]. On the contrary, other studies found that the opioid could promote the survival of tumor cells [ 13 – 18 ]. In a clinically relevant dose, morphine could promote tumor neovascularization in a breast tumor xenograft model in mice, which led to tumor progression [ 16 ].…”

“…Morphine also displayed the effects that can trigger the proliferation of glioblastoma T98G cell [ 17 ]. In addition, as another opioid receptor agonist, remifentanil possesses the capability of increasing cellular respiration of human hepatocytes and inhibiting tumor necrosis factor α (TNF-α) induced mitochondrial dysfunction [ 18 ].…”

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