ascorbic-acid and methylamine

Pretreatment of cultured hepatocytes with the ferric iron chelator deferoxamine prevents the killing of the cells by tert-butyl hydroperoxide (TBHP). Incubation of the deferoxamine-pretreated hepatocytes in a serum-free medium containing only 0.25 nM iron restored the sensitivity of the cells to TBHP within 4 to 6 hr. An amino acid-free medium accelerated the restoration of sensitivity in parallel with an enhanced rate of degradation of 14C-prelabeled protein. By contrast, inhibitors of the autophagic degradation of protein, including chymostatin, 3-methyladenine, benzyl alcohol, colchicine, oligomycin, and methylamine, inhibited the restoration of sensitivity of deferoxamine-treated hepatocytes to TBHP in parallel with their inhibition of protein degradation. With chymostatin, 3-methyladenine, benzyl alcohol, and colchicine, there was a parallel dose dependency of both the inhibition of protein turnover and the inhibition of the restoration of sensitivity to TBHP. Ascorbic acid, known to specifically retard the autophagic degradation of ferritin, inhibited the restoration of sensitivity to TBHP without effect on the general rate of protein turnover. None of the agents studied had any protective effect on the toxicity of TBHP for hepatocytes that were not pretreated with deferoxamine. These data indicate that the autophagic degradation of protein generates a pool of ferric iron required for the killing of cultured hepatocytes by TBHP.

Topics: Adenine; Amino Acids; Animals; Ascorbic Acid; Autophagy; Benzyl Alcohol; Benzyl Alcohols; Cell Survival; Cells, Cultured; Colchicine; Deferoxamine; Ferric Compounds; Ferritins; Liver; Methylamines; Oligomycins; Oligopeptides; Oxidation-Reduction; Peroxides; Phagocytosis; Proteins; Rats; Rats, Inbred Strains; tert-Butylhydroperoxide

Most inanimate systems are build of closed-shell molecules in which electrons lack excitability and mobility. These electrons can be rendered reactive and mobile by taking out some of them, desaturating the system electronically. Single electrons can be taken out of molecules by transfer to an external acceptor, creating two radicals that form a biradical having no net charge. The living state is such an electronically desaturated state. The universal electron acceptor of the biosphere is oxygen. Before light and O2 appeared, a weak electron acceptor could occur through linkage of two C=O groups to glyoxal and addition of a methyl group. The resulting methylglyoxal, being a weak acceptor, could lead to only a low degree of desaturation and thus to formation of only the simple life forms extant during this dark and anaerobic period--the alpha period. During the subsequent aerobic beta period, more highly differentiated life forms could develop because of occurrence of O2, a strong electron acceptor leading to a greater degree of desaturation. When dividing, however, beta-type cells return partially to the proliferative alpha state. The process of electron (charge) transfer, described here in two models, depends on the dielectric constant of the medium and the relative concentration of SH and methylglyoxal. Structure-building proteins that perform the main biological functions carry with them this chemical mechanism of their desaturation. Central to the mechanism is the NH2 of lysine that attaches a methylglyoxal. Through folding of the side chain, the CO groups of resulting Schiff bases can come in touch with the NH's of the peptide chain and accept electrons from it, desaturating it. Ascorbic acid is the catalyst of this charge transfer, which brings protein into the living state. Purified protein is inanimate matter. Manganese and oxygen form part of the chemical mechanism of desaturation, and the charge transfer reactions studied were found to be autocatalytic. It follows from the above observations that a cancer cell is a cell trapped in the alpha state.

Topics: Aldehydes; Ascorbic Acid; Biological Evolution; Chemical Phenomena; Chemistry; Electric Conductivity; Electron Spin Resonance Spectroscopy; Electron Transport; Ethylenediamines; Glutathione; Lysine; Methylamines; Mixed Function Oxygenases; Neoplasms; Origin of Life; Oxygen; Proteins; Pyruvaldehyde