Dopamine and uric acid act as antioxidants in the repair of DNA radicals: implications in Parkinson's disease.

Dopamine (DA) and uric acid (UA) have been found to undergo a protective reaction effecting the fast chemical repair of oxidative free-radical damage to DNA. This antioxidant reaction does not occur with normal concentrations of other, more abundant, antioxidants and our findings suggest that DA and UA are important for the preservation of the DNA in certain brains cells per se. These studies point to the need for drugs that undergo a similar antioxidant reaction with DNA radicals to prevent or arrest DNA damage associated with Parkinson's disease when the levels of DA and UA fall.

Enhanced conversion of DNA radical damage to double strand breaks by 1,2,4-benzotriazine 1,4-dioxides linked to a DNA binder compared to tirapazamine.

Targeting the anticancer compound tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide; TPZ) to DNA by appended binding units has been found to greatly increase the free radical-induced production of both single and double strand breaks under hypoxia compared to TPZ itself. The (*)OH radical, produced upon the radiolysis of aqueous solutions, was used to damage plasmid DNA, and both types of strand breaks were quantified in the absence and presence of TPZ and analogues. Targeted analogues of TPZ show increases of 12-18-fold in single strand breaks, and 60-110-fold in double strand breaks, as compared with TPZ itself. The observed increased formation of double strand breaks under hypoxia is the likely mechanism for the large increase in potency previously demonstrated for a similarly targeted analogue of TPZ as a bioreductive drug (Delahoussaye et al. (2003) Biochem. Pharmacol. 65, 1807-1815). The one-electron reduction potential of the two-electron reduced metabolite of TPZ (the 1-oxide, SR 4317) has been measured as -568 +/- 9 mV, which is sufficiently high to oxidize carbon-centered radicals such as those formed on the sugar moiety of DNA. Targeting the 1-oxide moiety to DNA resulted in a ca. 50% increase in single strand breaks over that seen for TPZ without the dramatic increase in double strand breaks seen for the similarly targeted benzotriazine 1,4-dioxides. These studies support the mechanism by which the reduction of TPZ to an oxidizing radical leads to free radical damage on DNA that can be further oxidized by TPZ or SR4317 (and especially well by DNA-targeted analogues) to yield lesions resulting in strand breakage. The targeting of benzotriazine 1,4-dioxide analogues to DNA by appending binding units to the compounds thus represents an efficient system for inducing strand breaks in DNA.