Oximes, including
2-pyridinealdoxime methiodide (2-PAM), are reactivators of
acetylcholinesterase (AChE) inhibited by
organophosphate poisoning. Unfortunately, their clinical use has been limited by their toxicity. To investigate the mechanism of this toxicity, the effects of
oximes on the
enzymes choline oxidase (ChOD) and
cytochrome c oxidase (CyCOD) of the respiratory chain in mitochondria were examined. The
oximes 2-PAM,
obidoxime, and
diacetylmonoxime significantly (P<0.01) inhibited ChOD activity, and the extent of inhibition correlated with the ability to reactivate inhibited AChE. When ChOD activity in mitochondrial extracts was tested,
2-PAM inhibited the activity by 75%,
obidoxime and
diacetylmonoxime did not significantly inhibit it, and 4-[(hydroxy-imino)methyl]-1-decylpyridinium
bromide (4-PAD), which has greater toxicity, increased the amount of product generated in the assay to approximately 200% of normal levels. Similarly,
2-PAM inhibited the activity of CyCOD in mitochondrial extracts whereas
obidoxime and
diacetylmonoxime did not. One explanation for these findings is that, in addition to their inhibition of mitochondrial
oxidases, the
oximes may produce excessive
reactive oxygen species such as H(2)O(2) in the mitochondrial fraction, which may account for some of their toxicity. This is a preliminary report related to the toxicities of
oximes that may participate in the inactivation of mitochondrial
oxidase enzymes. This hypothesis should be further investigated by in vivo study, including kinetic determination and
free radical work.