Succinate dehydrogenase activity regulates PCB3-quinone-induced metabolic oxidative stress and toxicity in HaCaT human keratinocytes

• Published in: Archives of toxicology Vol. 90; no. 2; pp. 319 - 332
• Main Authors: Xiao, Wusheng, Sarsour, Ehab H., Wagner, Brett A., Doskey, Claire M., Buettner, Garry R., Domann, Frederick E., Goswami, Prabhat C.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2016; Springer Nature B.V
• Subjects: Adenosine Triphosphate - metabolism; Benzoquinones - toxicity; Biomedical and Life Sciences; Biomedicine; Biphenyl Compounds - toxicity; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line; Dehydrogenases; Environmental Health; Hexokinase - metabolism; Humans; Keratinocytes - drug effects; Keratinocytes - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metabolism; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Molecular Toxicology; Occupational Medicine/Industrial Medicine; Oxidative stress; Oxidative Stress - drug effects; PCB; Pentose Phosphate Pathway - drug effects; Pharmacology/Toxicology; Polychlorinated biphenyls; Succinate Dehydrogenase - genetics; Succinate Dehydrogenase - metabolism; Thyroid Hormone-Binding Proteins; Thyroid Hormones - genetics; Thyroid Hormones - metabolism; Polychlorinated biphenyls; Glucose metabolism; Succinate dehydrogenase; G6PD; PCB3-quinone; Metabolic oxidative stress
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-014-1407-3

Polychlorinated biphenyls (PCBs) and their metabolites are environmental pollutants that are known to have adverse health effects. 1-(4-Chlorophenyl)-benzo-2,5-quinone (4-ClBQ), a quinone metabolite of 4-monochlorobiphenyl (PCB3, present in the environment and human blood) is toxic to human skin keratinocytes, and breast and prostate epithelial cells. This study investigates the hypothesis that 4-ClBQ-induced metabolic oxidative stress regulates toxicity in human keratinocytes. Results from Seahorse XF96 Analyzer showed that the 4-ClBQ treatment increased extracellular acidification rate, proton production rate, oxygen consumption rate and ATP content, indicative of metabolic oxidative stress. Results from a q-RT-PCR assay showed significant increases in the mRNA levels of hexokinase 2 ( hk2 ), pyruvate kinase M2 ( pkm2 ) and glucose-6-phosphate dehydrogenase ( g6pd ), and decreases in the mRNA levels of succinate dehydrogenase (complex II) subunit C and D ( sdhc and sdhd ). Pharmacological inhibition of G6PD-activity enhanced the toxicity of 4-ClBQ, suggesting that the protective function of the pentose phosphate pathway is functional in 4-ClBQ-treated cells. The decrease in sdhc and sdhd expression was associated with a significant decrease in complex II activity and increase in mitochondrial levels of ROS. Overexpression of sdhc and sdhd suppressed 4-ClBQ-induced inhibition of complex II activity, increase in mitochondrial levels of ROS, and toxicity. These results suggest that the 4-ClBQ treatment induces metabolic oxidative stress in HaCaT cells, and while the protective function of the pentose phosphate pathway is active, inhibition of complex II activity sensitizes HaCaT cells to 4-ClBQ-induced toxicity.