Quercetin prevents methotrexate-induced hepatotoxicity without interfering methotrexate metabolizing enzymes in liver of mice

Abstract

Drug-herb interactions are of great concern that may lead to increased side effects and decreased efficacy of the drugs. This study examined the effect of quercetin (QE) on the microsomal drug metabolizing and antioxidant systems in methotrexate (MX) treated mice, and also determined whether these substance affect the toxicity or detoxification of MX. Administration of MX at 10 mg/kg/day, i.m. for consecutive 3 days (on 7, 8 and 9. days of experiment) impaired antioxidant mechanisms and caused substantial increases in the levels liver injury markers in serum. Pretreatment with QE (50 mg/kg/day, p.o. for 10 days) inhibited MX-induced liver injury and oxidative stress by decreasing microsomal lipid peroxidation, increasing cellular glutathione content and maintaining the levels of antioxidant enzymes close to control values. MX markedly (P<0.05) decreased the activity of the hepatic phase I enzymes cytochrome P450 reductase, cytochrome b5 reductase, aniline hydroxylase and aldehyde oxidase. In general, administration of QE in combination with MX did not significantly (P>0.05) affect these enzyme activities. This is especially noteworthy in terms of aldehyde oxidase which is the key cytosolic enzyme in MX metabolism. Administration of QE along with MX significantly (p<0.05) increased the activity of the phase II enzymes glutathione S-transferase and DT-diaphorase relative to the MX treated group. Based on these results, the combination of QE or VA with MX therapy may represent a novel and highly effective strategy for reducing MX hepatotoxicity, without altering the outcome of MX metabolisim.