ffects of green and black tea biocomposites on endogenous synthesis, metabolism and genotoxic effect of carcinogenic N-nitrosodimethylamine

Aim: To study the modifying effect of green and black tea biocomposites on endogenous synthesis and genotoxic action of the carcinogenic N-nitrosodimethylamine. Methods: Green and black tea biocomposites were administered to the white inbred rats in vivo. Amidopyrine and sodium nitrite were used as N-nitrosodimethylamine precursors and 4-methylpyrazol as an inhibitor of its metabolism. N-nitrosodimethylamine (blood, daily urine and reaction mixture), nitrites and nitrates (daily urine) levels were measured. Genotoxic action was tested by formation of DNA single-strand breaks in hepatocytes. Results: In in vitro system, biocomposites increased N-nitrosodimethylamine synthesis in neutral medium and decreased in acid conditions. In vivo, black tea biocomposite consumption resulted in enhanced background level of DNA single-strand breaks in rats hepatocytes and higher genotoxic effect upon administration of N-nitrosodimethylamine precursors. The levels of N-nitrosodimethylamine in blood and urine of experimental animals were increased after precursors’ administration. In contrast, green tea biocomposite significantly decreased background level of DNA single-strand breaks. However, there was no protective action of this food supplement at the N-nitrosodimethylamine, precursors’ administration. 4-methylpyrazol administration did not increase N-nitrosodimethylamine excretion in urine, while this effect was observed in control and black tea biocomposite groups. Conclusions: The effects of green tea and black tea biocomposites on N-nitrosodimethylamine synthesis in in vitro system are unidirectional and depend on biocomposites’ concentration and acidity of the medium. Long-term consumption of black tea biocomposite resulted in intensification of endogenous N-nitrosodimethylamine synthesis and increased damage of the hepatocytes’ DNA. As to the green tea biocomposite, the obtained results allow us to suggest that this biocomposite enhanced N-nitrosodimethylamine metabolism.Цель: изучить модифицирующий эффект биокомпозитов из зеленого и черного чая на эндогенный синтез и генотоксическое действие канцерогенного N-нитрозодиметиламина. Методы: в эксперименте in vivo белые нелинейные крысы получали биокомпозиты из зеленого и черного чая. Амидопирин и нитрит натрия использовали в качестве предшественников N-нитрозодиметиламина и 4-метилпиразол в качестве ингибитора его метаболизма. Измеряли содержание N-нитрозодиметиламина (кровь, суточная моча и реакционная смесь), нитритов и нитратов (суточная моча). Генотоксическое действие оценивали по образованию однонитевых разрывов ДНК в гепатоцитах. Результаты: в системе in vitro биокомпозиты повышали синтез N-нитрозодиметиламина при нейтральной кислотности реакционной среды и снижали его в кислых условиях. В эксперименте in vivo употребление крысами биокомпозита из черного чая приводило к повышению уровня однонитевых разрывов ДНК в гепатоцитах и повышало генотоксический эффект от введения предшественников N-нитрозодиметиламина. После введения предшественников содержание N-нитрозодиметиламина в крови и моче было повышено. Наоборот, биокомпозит из зеленого чая значительно снижал фоновый уровень однонитевых разрывов ДНК. Однако не отмечали защитного действия этой пищевой добавки при введении предшественников N-нитрозодиметиламина. Введение 4-метилпиразола не приводило к повышенной экскреции N-нитрозодиметиламина с мочой, хотя этот эффект отмечали в контрольной группе и группе с назначением биокомпозита из черного чая. Выводы: в системе in vitro биокомпозиты из зеленого и черного чая однонаправлено влияли на синтез N-нитрозодиметиламина, а их эффекты зависели от кислотности реакционной среды и концентрации в ней биокомпозитов. Длительное употребление биокомпозита из черного чая приводило к интенсификации эндогенного синтеза N-нитрозодиметиламина и повышало уровень повреждений ДНК в гепатоцитах. Результаты, полученные относительно биокомпозита из зеленого чая, позволяют нам предположить, что он повышал метаболизм N-нитрозодиметиламина

Green tea, red wine and lemon extracts reduce experimental tumor growth and cancer drug toxicity

Aim: To evaluate antitumor effect of plant polyphenol extracts from green tea, red wine lees and/or lemon peel alone and in combination with antitumor drugs on the growth of different transplanted tumors in experimental animals. Materials and Methods: Green tea extract (GTE) was prepared from green tea infusion. GTE-based composites of red wine (GTRW), lemon peel (GTRWL) and/or NanoGTE as well as corresponding nanocomposites were prepared. The total polyphenolics of the different GTE-based extracts ranged from 18.0% to 21.3%. The effects of GTE-based extracts were studied in sarcoma 180, Ehrlich carcinoma, B16 melanoma, Ca755 mammary carcinoma, P388 leukemia, L1210 leukemia, and Guerin carcinoma (original, cisplatin-resistant and doxorubicin-resistant variants). The extracts were administered as 0.1% solution in drinking water (0.6–1.0 mg by total polyphenolics per mouse per day and 4.0–6.3 mg per rat per day). Results: Tumor growth inhibition (TGI) in mice treated with NanoGTE, cisplatin or cisplatin + NanoGTE was 27%, 55% and 78%, respectively, in Sarcoma 180%, 21%, 45% and 59%, respectively, in Ehrlich carcinoma; and 8%, 13% and 38%, respectively in B16 melanoma. Composites of NanoGTE, red wine, and lemon peel (NanoGTRWL) enhanced the antitumor effects of cyclophosphamide in mice with Ca755 mammary carcinoma. The treatment with combination of NanoGTE and inhibitors of polyamines (PA) synthesis (DFMO + MGBG) resulted in significant TGI of P388 leukemia (up to 71%) and L1210 leukemia. In rats transplanted with Guerin carcinoma (parental strain), treatment with GTRW or GTE alone resulted in 25–28% TGI vs. 55–68% TGI in cisplatin-treated animals. The inhibition observed in the case of combination of GTE or GTRW with cisplatin was additive giving 81–88% TGI. Similar effects were observed when combinations of the cytostatics with GTE (or ­NanoGTE) were tested against cisplatin- or doxorubicin-resistant Guerin carcinoma. Moreover, the plant extracts lowered side toxicity of the drugs. Treatment with GTE, NanoGTE, and NanoGTRW decreased the levels of malondialdehyde in heart, kidney and liver tissue of experimental animals, as well as the levels of urea and creatinine in blood serum, increased erythrocyte and platelet counts, hemoglobin content, and decreased leucocyte counts. Conclusion: The obtained data indicate the prospects for further deve­lopment of GTE and corresponding nanocomposites as auxiliary agents in cancer chemotherapy. Key Words: polyphenolic plant extracts, antitumor effect, cancer therapy

GREEN TEA, RED WINE AND LEMON EXTRACTS REDUCE EXPERIMENTAL TUMOR GROWTH AND CANCER DRUG TOXICITY

Aim: To evaluate antitumor effect of plant polyphenol extracts from green tea, red wine lees and/or lemon peel alone and in combination with antitumor drugs on the growth of different transplanted tumors in experimental animals. Materials and Methods: Green tea extract (GTE) was prepared from green tea infusion. GTE-based composites of red wine (GTRW), lemon peel (GTRWL) and/or NanoGTE as well as corresponding nanocomposites were prepared. The total polyphenolics of the different GTE-based extracts ranged from 18.0% to 21.3%. The effects of GTE-based extracts were studied in sarcoma 180, Ehrlich carcinoma, B16 melanoma, Ca755 mammary carcinoma, P388 leukemia, L1210 leukemia, and Guerin carcinoma (original, cisplatin-resistant and doxorubicin-resistant variants). The extracts were administered as 0.1% solution in drinking water (0.6–1.0 mg by total polyphenolics per mouse per day and 4.0–6.3 mg per rat per day). Results: Tumor growth inhibition (TGI) in mice treated with NanoGTE, cisplatin or cisplatin + NanoGTE was 27%, 55% and 78%, respectively, in Sarcoma 180%, 21%, 45% and 59%, respectively, in Ehrlich carcinoma; and 8%, 13% and 38%, respectively in B16 melanoma. Composites of NanoGTE, red wine, and lemon peel (NanoGTRWL) enhanced the antitumor effects of cyclophosphamide in mice with Ca755 mammary carcinoma. The treatment with combination of NanoGTE and inhibitors of polyamines (PA) synthesis (DFMO + MGBG) resulted in significant TGI of P388 leukemia (up to 71%) and L1210 leukemia. In rats transplanted with Guerin carcinoma (parental strain), treatment with GTRW or GTE alone resulted in 25–28% TGI vs. 55–68% TGI in cisplatin-treated animals. The inhibition observed in the case of combination of GTE or GTRW with cisplatin was additive giving 81–88% TGI. Similar effects were observed when combinations of the cytostatics with GTE (or ­NanoGTE) were tested against cisplatin- or doxorubicin-resistant Guerin carcinoma. Moreover, the plant extracts lowered side toxicity of the drugs. Treatment with GTE, NanoGTE, and NanoGTRW decreased the levels of malondialdehyde in heart, kidney and liver tissue of experimental animals, as well as the levels of urea and creatinine in blood serum, increased erythrocyte and platelet counts, hemoglobin content, and decreased leucocyte counts. Conclusion: The obtained data indicate the prospects for further deve­lopment of GTE and corresponding nanocomposites as auxiliary agents in cancer chemotherapy. Key Words: polyphenolic plant extracts, antitumor effect, cancer therapy