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Title:   Author  item
                                            WHEELOCK, C. - UCD, ENTOMOLOGY DEPT.item
                                            FORSHED, JENNY - KAROLINSKA UNIV. SOLNAitem
                                            GOTO, SUSUMU - KYOTO UNIV. JAPANitem
                                            HAMMOCK, BRUCE - UCD, DEPT. ENTOMOLOGYitem
                                            Newman, John
  Submitted to: Chemical Research in Toxicology
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 1/1/2008
                                    Publication  Date: 2/6/2008
                                    Citation: Wheelock, C.E., Forshed, J., Goto, S., Hammock, B.D., Newman, J.W. 2008. Effects of pyridine exposure upon structural lipid metabolism in Swiss Webster mice. Chemical Research in Toxicology. 21;583-590, 2008.Interpretive Summary: Chemicals which induce cytochrome P450 2E1 can produce oxidative damage to cellular membranes however specific effects on cellular lipids are not well understood. The effect of pyridine exposure on an array of brain, heart, liver and adipose tissue lipids was investigated to improve our understanding of these processes.  Pyridine altered the level and composition of lipids involved in membrane structure (i.e. sphingomyelin, phosphotidylethanolamine, plasmalogens), energy metabolism (i.e. free fatty acids) and long-chain fatty acid transport (i.e. cholesterol esters) in a tissue specific manner. Heart and brain sphingomyelins were structurally altered, while in the liver this lipid class increased as a whole. In the heart, pyridine exposure also produced a 40% increase in free fatty acids, a primary energy source in this tissue, and depleted the ether-linked plasmalogens in the primary lipid of the inner mitochondrial membrane. Brain phosphotidylethanolamine pools were also depleted in plasmalogens. Together, these results suggest that plasmalogens can serve as membrane associated antioxidants in both the brain and cardiac mitochondria. The responses in the brain and heart suggest that these extra-hepatic tissues should be the focus of future studies on the toxicity of pyridine and other CYP 2E1 inducers.
                                Technical Abstract: Pyridine is a prototypical inducer of cytochrome P450 (CYP) 2E1, an enzyme associated with cellular oxidative stress and membrane damage. To better understand the effect of this treatment on cellular lipids, the influence of pyridine exposure (100 mg/kg/day i.p. for 5 days) on fatty acids, fatty esters, and fatty alcohol ethers in brain, heart, liver and adipose tissue from male Swiss-Webster mice was investigated. Lipid levels in cholesterol esters, triglycerides, free fatty acids, cardiolipin, sphingomyelin and glycerylphospholipids were quantified. Pyridine altered the level and composition of lipids involved in membrane structure (i.e. sphingomyelin, PE, plasmalogens), energy metabolism (i.e. free fatty acids) and long-chain fatty acid transport (i.e. cholesterol esters) in a tissue specific manner. Subtle changes in cholesterol esters were observed in all tissues. Sphingomyelin in the brain and heart were depleted in monounsaturated fatty acids, while the liver sphingomyelin concentrations increased. Pyridine exposure also increased heart free fatty acids 40%, enriched cardiac phosphatidylethanolamine in long chain polyunsaturated fatty acids, and depleted cardiolipin-associated plasmalogens.  Phosphatidylethanolamines in the brain were also enriched in both saturated fatty acids and polyunsaturated fatty acids, but were depleted in plasmalogens. These findings suggest that plasmalogens can serve as antioxidants in both the brain and cardiac mitochondria. In addition, altered levels of hepatic sphingomyelins were consistent with an early adaptive response to heightened bile acid clearance. The responses in the brain and heart suggest that these tissues should be the focus of future studies on the toxicity of pyridine and other CYP 2E1 inducers.


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