The antioxidant effect of lovastatin on phagocyte-induced DNA damage: implications for cancer prevention

Lovastatin is one of a series of HMG-CoA reductase inhibitors used in the treatment of hypercholesterolemia. It may also inhibit atheroma formation by inhibiting the oxidation of low density lipoproteins (LDLs). We investigated the antioxidant properties of lovastatin and its effect on phagocyte-induced genotoxicity in mammalian cells. In a cytochrome c reduction assay using 106 phorbol ester-induced phagocytes as a positive control, lovastatin (10 microM) in its naturally occurring lactone form, had no effect. When converted to its acid form, however, superoxide anion formation was inhibted by 36%. Similarly, lovastatin in its acid form completely inhibited H2O2 formation by stimulated phagocytes. Using the fluorometric analysis of DNA unwinding, single-strand breakage was assayed in MRC-5 lung cells exposed to 106 human phagocytes +/- lovastatin (10 microM, 5 min. incubation). Stimulated phagocytes induced a decrease in double-stranded DNA to 48% of control values which, in the presence of lovastatin, reverted to 91% of control values. Lovastatin acts as an antioxidant by decreasing oxygen radical production by human phagocytes and may be important in abrogating the carcinogenic effect of chronic inflammation.