Inhibition of lysyl hydroxylase by malathion and malaoxon

The inhibition of lysyl hydroxylation in newly synthesized collagen by mala thion and its oxidation product malaoxon were studied with cultured rat fet al lung fibroblasts, Exposure of these cells to 125 muM malathion or malaox on for 96 h resulted in a 25 and a 30% decrease in the ratio of hydroxylate d lysine/lysine residues, respectively, in acid hydrolyzed cell lysates com pared to control values. This relative decrease in hydroxylysine was not ca used by cytotoxicity or changes in total collagen content, which were found to remain constant as measured by Alamar Blue metabolism and Sircol dye bi nding assays. Direct inhibition of lysyl hydroxylase by malathion and malao xon was observed using an in vitro enzyme assay with recombinant lysyl hydr oxylase with a baculoviral system. The IC50 values for malathion and malaox on were estimated to be approximately 60 and 45 muM, respectively. These ob served IC50 values are consistent with calculated values for the intracellu lar concentration of malathion in the cell culture experiments. These resul ts support a significant role for inhibition of lysyl hydroxylase activity as causing, or contributing to, the teratogenic effects of malathion and ma laoxon. (C) 2001 Academic Press.