Role of Quercetin in chemoprevention against wide range of carcinogens and mutagens

Quercetin is a ubiquitous plant flavoniod with significant pharmacological and clinical activity. In this study we determined to demonstrate the protective role of quercetin against range of mutagens and carcinogens in a combination of <em>in vitro</em> and <em>in vivo</em> studies via different mechanisms. Quercetin demonstrated significant protective role against sodium azide, benzo(a)pyrene, cyclophosphamide monohydrate, methyl methane sulphonate and etoposide compared to other mutagens. Quercetin is effective in both <em>in vitro</em> and <em>in vivo</em> test conditions and also in the presence as well as in the absence of metabolic activation system (Rat liver S9). Auto oxidation, antioxidant properties, inhibition of pro-mutagens metabolism by CYP1A activity and multiple antimutagenic and adaptive response, mechanisms of quercetin may account for its protective role in cancer prevention. In conclusion, the results clearly indicate that quercetin plays a significant role against mutagens that act by direct DNA binding (form DNA adducts), pro-mutagens and alkylating agents with free radical generation; which could be the rationale for its potent anticancer activity against particular cancer types.

In vivo and in vitro effects of pentavalent antimony on mouse liver cytochrome P450s

Pentavalent antimonial (Sb5+) drugs such as meglumine antimoniate (MA) are the mainstay treatment of leishmaniases in developing countries. The effects of these compounds on drug-metabolizing enzymes have not been characterized and their potential pharmacokinetic interactions with other drugs are therefore unknown. The present study investigated whether treatment with MA (300 mg Sb5+/kg body weight/day, subcutaneously) for 24 days affected the activities of cytochrome P450 (CYP)1A (ethoxyresorufin- O-deethylase), CYP2A5 (coumarin 7-hydroxylase), CYP2E1 ( p-nitrophenol-hydroxylase), CYP2B9/10 (benzyloxy-resorufin- O-debenzylase), or CYP3A11 (erythromycin- N-demethylase) in the livers of Swiss Webster (SW) and DBA-2 male and female mice. The results showed that CYP2A5-, CYP2E1-, and CYP3A11-catalyzed reactions were unaffected by MA treatment. A decrease in CYP2B9/10 activity was noted in DBA-2 females (but not males) and was not observed in SW males or females. However, repeated MA administration reduced mouse liver CYP1A activity. CYP1A2 messenger RNA (mRNA) levels were not affected by MA and in vitro exposure of mouse liver microsomes to Sb3+ and Sb5+ did not reduce CYP1A activity. These findings suggested that in vivo treatment with Sb5+ drugs depressed CYP1A activity, without downregulating CYP1A2 mRNA expression. Since in vitro treatment of liver microsomes failed to inhibit CYP1A activity, this effect may require intact cells.

Effects of hypericin on the oxidative stress and modulation of cytochrome P450 (CYP1A) activity in microsomes

Hypericin is a pigment present in the widely distributed medicinal plant Hypericum perforatum L. (Hypericaceae). In our research, hypericin was found to be an inhibitor of NADPH/Fe2+ induced microsomal lipid peroxidation and NADPH-dependent lucigenin chemiluminescence emission in vitro. Hypericin also inhibited the microsomal CYP1Adependent 7-ethoxyresorufin O-deethylase (EROD) which participates in the metabolic activation of xenobiotics including chemical carcinogens.

In VitroGender-Dependent Inhibition of Porcine Cytochrome P450 Activity by Selected Flavonoids and Phenolic Acids

We investigated gender-related differences in the ability of selected flavonoids and phenolic compounds to modify porcine hepatic CYP450-dependent activity. Using pools of microsomes from male and female pigs, the inhibition of the CYP families 1A, 2A, 2E1, and 3A was determined. The specific CYP activities were measured in the presence of the following selected compounds: rutin, myricetin, quercetin, isorhamnetin,p-coumaric acid, gallic acid, and caffeic acid. We determined that myricetin and isorhamnetin competitively inhibited porcine CYP1A activity in the microsomes from both male and female pigs but did not affect the CYP2A and CYP2E1. Additionally, isorhamnetin competitively inhibited CYP3A in both genders. Noncompetitive inhibition of CYP3A activity by myricetin was observed only in the microsomes from male pigs, whereas CYP3A in female pigs was not affected. Quercetin competitively inhibited CYP2E1 and CYP1A activity in the microsomes from male pigs and irreversibly CY3A in female pigs. No effect of quercetin on CYP2E1 was observed in the microsomes from female pigs. Neither phenolic acids nor rutin affected CYP450 activities. Taken together, our results suggest that the flavonoids myricetin, isorhamnetin, and quercetin may affect the activities of porcine CYP1A, CYP3A, and CYP2E1 in a gender-dependent manner.