Snake venom LAAOs have been reported to exhibit a wide range of pharmacological activities, including cytotoxic,
edema-inducing, platelet aggregation-inducing/platelet aggregation-inhibiting, bactericidal and
antiviral activities. A heat-stable form of
l-amino acid oxidase isolated from king cobra (
Ophiophagus hannah) venom (
OH-LAAO) has been shown to exhibit very potent cytotoxicity against human tumorigenic cells but not in their non-tumorigenic counterparts, and the cytotoxicity was due to the apoptosis-inducing effect of the
enzyme. In this work, the molecular mechanism of cell death induced by
OH-LAAO was investigated. The
enzyme exerts its apoptosis-inducing effect presumably via both intrinsic and extrinsic pathways as suggested by the increase in
caspase-8 and -9 activities.
Oligonucleotide microarray analysis showed that the expression of a total of 178 genes was significantly altered as a result of oxidative stress induced by the
hydrogen peroxide generated by the
enzyme. Of the 178 genes, at least 27 genes are involved in apoptosis and cell death. These alterations of gene expression was presumably caused by the direct cytotoxic effect of H2O2 generated during the enzymatic reaction, as well as the non-specific oxidative modifications of signaling molecules that eventually lead to apoptosis and cell death. The very substantial up-regulation of
cytochrome P450 genes may also contribute to the potent cytotoxic action of
OH-LAAO by producing excessive
reactive oxygen species (ROS). In conclusion, the potent apoptosis inducing activity of
OH-LAAO was likely due to the direct cytotoxic effect of H2O2 generated during the enzymatic reaction, as well as the non-specific oxidation of signalling molecules.