Figure 6
Proposed mechanism for B[a]P-induced hyperstimulatory metabolism and proliferative changes in Beas-2B cells. (a) B[a]P induces a metabolic shift from glycolysis to the Pentose Phosphate Pathway mediated by XRE-related transcription. Nucleotide ratio imbalance triggers post-translational modification of G6PDH by SIRT2 and transcriptional regulation by the XRE combine to restore NADPH levels required to supply microsomal metabolism of B[a]P, leading to reduction in glycolytic flux and transient reductions in mitochondrial membrane potential. (b) Constitutive CYP1 bioactivates B[a]P to a genotoxic metabolite, while B[a]P perpetuates CYP1 expression through XRE. Enhanced CYP1 metabolism further contributed to genotoxic insult, resulting in transient inter-S checkpoint initiation mediated through Chk1 and p53. Abbreviations: AhR, Aryl Hydrocarbon Receptor; B[a]P, Benzo[a]pyrene; CYP1, Cytochrome P450 Isoforms 1A1 and 1B1; G6PDH, Glucose-6-Phosphate Dehydrogenase. NAD+, Oxidized Nicotinamide Adenine Dinucleotide; NADP+, Oxidized Nicotinamide Adenine Dinucleotide Phosphate; NADPH, Reduced Nicotinamide Adenine Dinucleotide Phosphate; (p)-Chk1S345, Phospho-Checkpoint Kinase 1; (p)-P53S15, Phospho-P53; SIRT2, Sirtuin 2; XRE, Xenobiotic Response Element; ΔΨm, Mitochondrial Membrane Potential. 6AN, 6-Aminonicotinamide; AGK2, 2-cyano-3-[5-(2,5-dichlorophenyl)-2-furyl]-N-5-quinolinylacrylamide; CH223191, 1-Methyl-N-[2-methyl-4-[2-(2-methylphenyl)diazenyl]phen yl-1H-pyrazole-5-carboxamide; siRNA, Silencing RNA; αNF, Alpha-Naphthoflavone. AB, Alamar Blue; MTT, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; WST1, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium.
