Chemical pathology of homocysteine. IV. Excitotoxicity, oxidative stress, endothelial dysfunction, and inflammation.
This review considers recent advances in the chemical pathology of homocysteine in atherogenesis, oxidative metabolism, and carcinogenesis. Homocysteine is a potent excitatory neurotransmitter that binds to the N-methyl-D-aspartate (NMDA) receptor and leads to oxidative stress, cytoplasmic calcium influx, cellular apoptosis, and endothelial dysfunction. According to the adsorption-induction theory, cytoplasmic calcium influx leads to depletion of cellular adenosine triphosphate (ATP) by reaction with cytoplasmic phosphate, leading to calcium apatite deposition. Oxidative stress is caused by failure of ATP synthesis and accumulation of reactive oxygen radicals, theoretically because of inhibition of thioretinaco ozonide function within mitochondria and endoplasmic reticulum. The toxicity of oxygen difluoride is theoretically explained by the displacement of ozone from thioretinaco ozonide, leading to inhibition of cellular respiration. Depletion of thioretinaco ozonide from cellular membranes is suggested to underlie the carcinogenic and atherogenic effects of fluoride and other electrophilic carcinogens. In atherogenesis the acute inflammatory response is related to cellular apoptosis and necrosis, autoantibodies to proteins containing peptide-bound homocysteine and oxidized low-density lipoprotein (Ox-LDL), and microbial products and antigens originating from homocysteinylated LDL aggregates trapped within vasa vasorum of developing atherosclerotic plaques. The trapping of lipoprotein aggregates and obstruction of the lumen of vasa vasorum are enhanced by high tissue pressure and by endothelial dysfunction because of narrowing of the lumen by swollen and hyperplastic endothelial cells, leading to the creation of vulnerable plaques.
McCully
Kilmer S
KS
Veterans Affairs Medical Center, West Roxbury, MA 02132, USA. kilmer.mccully@va.gov
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D006710:Homocysteine / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D009369:Neoplasms / Q000209:etiology / Q000378:metabolism; D009420:Nervous System / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*
D006710:Homocysteine