Chemicalinduced Carcinogenesis

Nitrated compounds, polycyclic aromatic hydrocarbons, and carbon tetrachloride are established carcinogens used to assess mutagenicity in various experimental models. Anthocyanins have been reported to have antimutagenic activity toward these aforementioned compounds. Studies by Obi et al.97 revealed that anthocyanins extracted from the petals of Hibiscus rosasinensis protected against carbon tetrachloride-induced liver damage in rats. Carbon tetrachloride, a hepa-totoxin, is responsible for P450-induced trichloromethyl radical production and associated peroxidation of membrane lipids leading to extensive liver damage including liver cancer.97 Additionally, studies of the antimutagenic activity of fruit juices high in anthocyanins using the Ames test revealed blueberry juice to have one of the highest antimutagenic activities observed against polycyclic aromatic hydrocarbons.98 Furthermore, Tsuda et al.99 observed that the anthocyanin pelar-gonidin prevented the formation of nitrated tyrosine in vitro. Unfortunately, the above investigations were unable to determine the extent to which anthocyanins acted directly as scavengers or indirectly on the enzymes involved with xenobiotic metabolism.97

20.6.1 Phase I Xenobiotic Detoxification

Some flavonoids are potent inhibitors of the cytochrome P450 isozyme family CYP1A. CYP1A1 is responsible for the metabolic activation of carcinogens such as polycyclic aromatic hydrocarbons and nitrosamines.100 Le Marchand et al.10 determined an inverse association between the intake of flavonoids and lung cancer risk in a Hawaiian case-control study as mentioned above (Section 20.1.2, Flavonoids and Cancer). The researchers genotyped subjects for the P-450 enzyme variant allele CYP1A1 and suggested that the reduced risk of lung cancer was a result of a decreased bioactivation of carcinogens through the inhibition of the CYP1A1 isoform caused by flavonoids. Structure-activity relationship studies of anthocyanins suggest that the ortho-dihydroxyls of the B-ring play an important role in the antimutagenic activity of the anthocyanins.101 Additionally, Tsyrlov et al.102 speculated that the catechol moiety is likely responsible for the inhibition of cDNA-expression of the CYP1A P-450 family as a result of ligand-binding activity.

20.6.2 Phase II Xenobiotic Detoxification

Bioactive extracts, high in anthocyanins, from the Vaccinium species may have the potential to inhibit the initiation and promotion stages of carcinogenesis under in vitro conditions. Quinone reductase is an enzyme responsible for inactivating electrophilic carcinogens and potentially preventing metabolic activation prior to DNA binding. Crude extracts of the lowbush blueberry, cranberry, lingonberry, and bilberry (Vaccinium) were shown to have the ability to induce the Phase II xenobiotic detoxification enzyme quinone reductase, thus displaying the capacity to inhibit the initiation of chemically induced carcinogenesis.103,104 Extracts were further shown to actively inhibit ornithine decarboxylase, a rate-limiting enzyme in the synthesis of polyamines. Polyamine formation is believed to be associated with carcinogenesis as these compounds are formed in high quantities by rapidly proliferating cells.103

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