Mutagenic and carcinogenic potential of menadione.
Abstract:
Menadione (2-methyl-l,4-naphthoquinone) or vitamin K3 is a lipid-soluble substance and promotes the hepatic biosynthesis of blood clotting factors. Carcinogenic potential of menadione was determined by a DC polarography method in strictly anhydrous N,N-dimethylformamide (DMF) in the presence of alpha-lipoic acid. Superoxide anion formation was measured after incubation of rat lung, liver and kidney microsomes with menadione. The genotoxic potential of menadione was investigated using the unscheduled DNA synthesis (UDS) and alkaline elution assays. The parameter of potential menadione carcinogenicity tg alpha was 0.0025 indicating no carcinogenic activity of menadione. Superoxide anion was generated in a concentration- and time-dependent manner when menadione was incubated with microsomes. In the mammalian cells (A 549) used for alkaline elution and UDS assays, menadione was cytotoxic at concentrations above 20 nmol/ml. The use of S9 mix (metabolic activation) fractions decreased the cytotoxicity of menadione. In the concentration range of above 20 nmol/ml menadione was genotoxic in the UDS test in absence of metabolic activation. In the presence of metabolic activation the menadione-induced DNA damage and repair was greatly reduced. Treatment of A 549 lung cells with 4-nitroquinoline-N-oxide (NQO) caused significant formation of DNA single-strand breaks both in the absence and presence of metabolic activation. Treatment of A 549 lung cells with menadione caused formation of DNA single-strand breaks in the absence of S9 mix. In the presence of metabolic activation menadione caused no significant formation of DNA strand breaks. Menadione-induced DNA repair in A 549 cells was concentration-, time-, and temperature- dependent. Measurement of unscheduled DNA (UDS) synthesis (repair) following treatment with NQO and menadione yielded strong UDS responses in the absence of S9 mix. Taken together the results of these studies suggest the mutagenic potential of NQO and menadione. These results indicate that menadione undergoes redox cycling with formation of reactive oxygen species which cause DNA damage and repair without having a carcinogenic potential.