Inhibition of lysyl hydroxylase by malathion and malaoxon.
The inhibition of lysyl hydroxylation in newly synthesized collagen by malathion and its oxidation product malaoxon were studied with cultured rat fetal lung fibroblasts. Exposure of these cells to 125 microM malathion or malaoxon for 96 h resulted in a 25 and a 30% decrease in the ratio of hydroxylated lysine/lysine residues, respectively, in acid hydrolyzed cell lysates compared to control values. This relative decrease in hydroxylysine was not caused by cytotoxicity or changes in total collagen content, which were found to remain constant as measured by Alamar Blue metabolism and Sircol dye binding assays. Direct inhibition of lysyl hydroxylase by malathion and malaoxon was observed using an in vitro enzyme assay with recombinant lysyl hydroxylase with a baculoviral system. The IC50 values for malathion and malaoxon were estimated to be approximately 60 and 45 microM, respectively. These observed IC50 values are consistent with calculated values for the intracellular concentration of malathion in the cell culture experiments. These results support a significant role for inhibition of lysyl hydroxylase activity as causing, or contributing to, the teratogenic effects of malathion and malaoxon.
Samimi
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Pulmonary/Critical Care Medicine, University of California, Davis, California, 95616, USA.
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D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000201:enzymology; D006900:Hydroxylation; D007306:Insecticides / Q000494:pharmacology*; D008168:Lung; D008239:Lysine / Q000378:metabolism; D008294:Malathion / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D007306:Insecticides; D011994:Recombinant Proteins; C100082:malaoxon; D003094:Collagen; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; D008239:Lysine; D008294:Malathion