Midpoint potential of the phenoxyl radical/phenol redox couple of phytocannabinoids as a diagnostic tool for analyzing their prooxidant action in the cell

The phenolic phytocannabinoids frequently exhibit a prooxidant activity, however, its significance in their toxic/therapeutic action remains unclear. On the other hand, the predominant prooxidant character of mammalian cell cytotoxicity of hydroxybenzenes is demonstrated by a negative dependence of the cytotoxicity on the midpoint redox potential of phenoxyl radical/phenol couple (E(Ph-O•/Ph-OH) or E27 at pH 7.0). However, the E27 values of phytocannabinoids are unknown. Here using quantum mechanical calculations and cyclic voltammetry, the E27 values of 10 phytocannabinoids containing resorcinol, 1-hydroxychromene or 1-hydroxychromane moieties were estimated to be 0.72 V- 0.82 V, i.e., close to or below that of resorcinol, 0.81 V. Using the above E27 values, it was found that the cytotoxicity of phytocannabinoids in MH22a cells follows the same two-parameter regression as that of model hydroxybenzenes, i.e., it increased with decreasing E27 and increasing octanol/water partition coefficient at pH 7.0 (log.D). The prooxidant nature of phytocannabinoid cytotoxicity was evidenced by the protective effects of antioxidants, and the potentiating effect of N,N’-bis(2-chloroethyl)-N-nitrosourea (BCNU). On the other hand, the in vitro activity of phytocannabinoids against Plasmodium falciparum FcB1 strain was much greater than that of model hydroxybenzenes, and did not follow the same correlation. Unlike the lipophilicity-independent activity of hydroxybenzenes, the antiplasmodial activity of phytocannabinoids showed a trend to increase with their log D. These findings enabled to suggest that the mammalian cell cytotoxicity of phytocannabinoids may be largely determined by their induced oxidative stress, but their antiplasmodial activity may be determined by other, as yet poorly characterized, factors.