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Toxicol Appl Pharmacol. 2017 Jan 1;314:1-11. doi: 10.1016/j.taap.2016.11.003. Epub 2016 Nov 9.

Sibutramine provokes apoptosis of aortic endothelial cells through altered production of reactive oxygen and nitrogen species.

Author information

1
Forensic Science Laboratory, Gifu Prefectural Police Headquarters, Gifu 500-8501, Japan.
2
Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
3
Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
4
Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan. Electronic address: matsunagat@gifu-pu.ac.jp.

Abstract

Overdose administration of sibutramine, a serotonin-noradrenalin reuptake inhibitor, is considered to elicit severe side effects including hypertension, whose pathogenic mechanism remains unclear. Here, we found that 48-h incubation with >10μM sibutramine provokes apoptosis of human aortic endothelial (HAE) cells. Treatment with the lethal concentration of sibutramine facilitated production of reactive oxygen species (ROS), altered expression of endoplasmic reticulum stress response genes (heat shock protein 70 and C/EBP homologous protein), and inactivated 26S proteasome-based proteolysis. The treatment also decreased cellular level of nitric oxide (NO) through lowering of expression and activity of endothelial NO synthase. These results suggest that ROS production and depletion of NO are crucial events in the apoptotic mechanism and may be linked to the pathogenesis of vasoconstriction elicited by the drug. Compared to sibutramine, its metabolites (N-desmethylsibutramine and N-didesmethylsibutramine) were much less cytotoxic to HAE cells, which hardly metabolized sibutramine. In contrast, both the drug and metabolites showed low cytotoxicity to hepatic HepG2 cells with high metabolic potency and expression of cytochrome P450 (CYP) 3A4. The cytotoxicity of sibutramine to HepG2 and Chang Liver cells was remarkably augmented by inhibition and knockdown of CYP3A4. This study also suggests an inverse relationship between sibutramine cytotoxicity and CYP3A4-mediated metabolism into the N-desmethyl metabolites.

KEYWORDS:

Apoptosis; Endothelial cell; Nitric oxide; Reactive oxygen species; Sibutramine

PMID:
27838152
DOI:
10.1016/j.taap.2016.11.003
[Indexed for MEDLINE]

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