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Glutathione traps formaldehyde by formation of a bicyclo[4.4.1]undecane adduct.

ABSTRACT: Glutathione forms complex reaction products with formaldehyde, which can be further modified through enzymatic modification. We studied the non-enzymatic reaction between glutathione and formaldehyde and identified a bicyclic complex containing two equivalents of formaldehyde and one glutathione molecule by protein X-ray crystallography (PDB accession number 2PFG). We have also used (1)H, (13)C and 2D NMR spectroscopy to confirm the structure of this unusual adduct. The key feature of this adduct is the involvement of the gamma-glutamyl alpha-amine and the Cys thiol in the formation of the bicyclic ring structure. These findings suggest that the structure of GSH allows for bi-dentate masking of the reactivity of formaldehyde. As this species predominates at near physiological pH values, we suggest this adduct may have biological significance.

SUBMITTER: Bateman R

PROVIDER: S-EPMC2932697 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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Glutathione traps formaldehyde by formation of a bicyclo[4.4.1]undecane adduct.

Bateman Raynard R Rauh Daniel D Shokat Kevan M KM

Organic & biomolecular chemistry 20070829 20

Glutathione forms complex reaction products with formaldehyde, which can be further modified through enzymatic modification. We studied the non-enzymatic reaction between glutathione and formaldehyde and identified a bicyclic complex containing two equivalents of formaldehyde and one glutathione molecule by protein X-ray crystallography (PDB accession number 2PFG). We have also used (1)H, (13)C and 2D NMR spectroscopy to confirm the structure of this unusual adduct. The key feature of this adduc ...[more]

PMID: 17912391

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Project description:Environmental carcinogens, such as polycyclic aromatic hydrocarbons (PAHs), require metabolic activation to DNA-reactive metabolites in order to exert their tumorigenic effects. Benzo[a]pyrene (B[a]P), a prototypic PAH, is metabolized by cytochrome P450 (P450) 1A1/1B1 and epoxide hydrolase to (-)-B[a]P-7,8-dihydro-7,8-diol (B[a]P-7,8-dihydrodiol). B[a]P-7,8-dihydrodiol then undergoes further P4501A1/1B1-mediated metabolism to the ultimate carcinogen, (+)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro-B[a]P (B[a]PDE), which forms DNA-adducts primarily with 2'-deoxyguanosine (dGuo) to form (+)-anti-trans-B[a]PDE-N(2)-dGuo (B[a]PDE-dGuo) in DNA. Pretreatment of cells with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to induce P4501A1/1B1 mRNA expression through the aryl hydrocarbon receptor (AhR) pathway. This causes increased B[a]PDE-dGuo formation in liver cells. In contrast, TCDD induction of H358 lung cells surprisingly caused a decrease in (-)-B[a]P-7,8-dihydrodiol-mediated (+)-B[a]PDE-dGuo adduct formation when compared with the non-TCDD-induced cells. Furthermore, treatment of the TCDD-induced cells with (±)-B[a]PDE also resulted in decreased (+)-B[a]PDE-dGuo adduct formation when compared with the non-TCDD-induced cells. These data suggested that it was a detoxification pathway that had been up-regulated rather than an activation pathway that had been down-regulated. LC-MS was used to analyze B[a]PDE-dGuo and B[a]PDE-GSH-adducts in H358 lung and HepG2 liver cells. There was a significant increase in the (-)-B[a]PDE-GSH-adduct with high enantiomeric excess after treatment of the TCDD-induced H358 cells with (±)-B[a]PDE when compared with the noninduced cells. This could explain why increased activation of (-)-B[a]P-7,8-dihydrodiol through TCDD up-regulation of P4501A1/1B1 did not lead to increased (+)-B[a]PDE-dGuo adducts in the H358 lung cells. In addition, TCDD did not induce B[a]PDE-GSH-adduct formation in HepG2 liver cells. (±)-B[a]PDE-GSH-adducts were formed at much lower levels in both TCDD-induced and noninduced HepG2 cells when compared with (-)-B[a]PDE-GSH-adducts in the H358 lung cells. Therefore, our study has revealed that there is a subtle balance between activation and detoxification of B[a]P in lung-derived compared with liver-derived cells and that this determines how much DNA damage occurs.

Dataset Information

Glutathione traps formaldehyde by formation of a bicyclo[4.4.1]undecane adduct.

Publications

Glutathione traps formaldehyde by formation of a bicyclo[4.4.1]undecane adduct.

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