Mercapturate metabolism of 4-hydroxy-2-nonenal in rat and human cerebrum.

4-Hydroxy-2-nonenal (HNE), a potent toxin formed in the brain from oxidation of polyunsaturated fatty acids, is increased in Alzheimer disease (AD), where it is a proposed effector of amyloid beta peptide-mediated neurotoxicity. Detoxification of HNE via the mercapturic acid pathway (MAP) is the primary means by which other organs, such as liver, limit its toxic effects. Here we examined the distribution and activity of MAP detoxification for HNE in cerebrum. Our results showed that rat cerebral cortex and especially synaptosomes were less well equipped to detoxify HNE via the MAP than liver. Glutathione transferases (GSTs) catalyze the committed step in the MAP; GST-mu and GST-pi, but not OST-alpha, were detected in neurons and astrocytes in cerebrum from AD patients and controls. MAP activity in frontal cortex of AD patients was modestly but significantly increased compared to controls. These data suggest that lipid peroxidation may present a greater toxic burden to cerebrum than to other organs, and that a component of response to injury in late stage AD is a slight increase in MAP activity.

Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis.

We used the hypomorphic Egfr(wa2) allele to genetically examine the impact of impaired epidermal growth factor receptor (Egfr) signaling on the Apc(Min) mouse model of familial adenomatous polyposis. Transfer of the Apc(Min) allele onto a homozygous Egfr(wa2) background results in a 90% reduction in intestinal polyp number relative to Apc(Min) mice carrying a wild-type Egfr allele. This Egfr effect is potentially synergistic with the actions of the modifier-of-min (Mom1) locus. Surprisingly, the size, expansion, and pathological progression of the polyps appear Egfr-independent. Histological examination of the ilea of younger animals revealed no differences in the number of microadenomas, the presumptive precursor lesions to gross intestinal polyps. Pharmacological inhibition with EKI-785, an Egfr tyrosine kinase inhibitor, produced similar results in the Apc(Min) model. These data suggest that normal Egfr activity is required for establishment of intestinal tumors in the Apc(Min) model between initiation and subsequent expansion of initiated tumors. The role of Egfr signaling during later stages of tumorigenesis was examined by using nude mice xenografts of two human colorectal cancer cell lines. Treatment with EKI-785 produced a dose-dependent reduction in tumor growth, suggesting that Egfr inhibitors may be useful for advanced colorectal cancer treatment.