Since flavonoids can produce a prooxidant effect in-vitro (see Table 15.3), their ability to induce cancer has been of concern. Quercetin has been of most concern due to its high redox activity; of all the flavonoids it produces the greatest mutagenetic effects in vitro, as discussed previously.
When quercetin is used with a carcinogen, it can increase carcinogen's effects (in this situation, quercetin acts as a tumor-promoting agent). For example, it enhanced the carcinogenic activity of 3-methylcholan-threne in mice and azoxymethane in rats.105,106 In the first study, quercetin was only active when it was co-injected subcutaneously with the carcinogen in the mice, and therefore these results have little relevance to oral administration. In the second, perhaps more relevant study, an oral dose of about 1.3 g/kg combined with the carcinogen decreased development of breast cancer in rats but increased that of colon cancer. It is reasonable to suppose that the very high concentration of the (reactive) aglycone in the intestines, in combination with the carcinogen, caused a local prooxidant effect that led to tumor development. The human equivalent of a 1.3-g/kg dose in rats is about 21 grams per day. Quercetin has also been reported to increase development of cancers outside the intestines; in one study, a dose of 12 g in the diet (as scaled to humans) increased the risk of pancreatic cancer in rats treated with a carcinogen.107
When quercetin was used alone, however, as it has been in many animal studies, results suggest the compound was not carcinogenic. In rats fed diets containing up to 5 percent quercetin (about 3.8 g/kg) for two years, no carcinogenic effects were observed, although benign kidney tumors did appear in some male rats.108,109 A lack of carcinogenic effects was also noted in hamsters and rats on a 10 percent quercetin diet for up to two years.110,111 In a review of a Japanese National Toxicology Program report concerning the long-term carcinogenic effect of quercetin in rats, the authors concluded that "therefore, although the data of [the program] do indicate possible carcinogenic activity, its risk potential for man on the basis of our present knowledge must be considered to be negligible."112 In fact, some studies have reported that quercetin produces anticar-cinogenic effects.113 For example, oral administration of a high quercetin dose (about 1.5 to 3.8 g/kg in the diet) inhibited the incidence and number of palpable breast cancers in rats injected with the carcinogen N-nitrosomethylurea.114
The general lack of carcinogenic effects by quercetin is likely for two reasons. First, quercetin occurs as conjugates in the plasma. As discussed in Appendix J, these conjugates are less reactive than the free compound. Second, although the doses used were very high (the human equivalent of about 24 to 120 grams per day), it is unlikely such high doses were completely absorbed or metabolized in the same way lower doses would be. At doses above about 1.8 grams per day, many compounds are either poorly absorbed or are metabolized quite differently than lower doses (see Appendix J); in some cases, high doses are heavily methylated, which severely restricts their ability to undergo redox reactions. Thus, it seems the body has built-in mechanisms that help prevent systemic prooxidant effects caused by high doses of orally administered flavonoids.
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