Biomedical subjects

Joshua D Lambert

Publications and source records attributed to Joshua D Lambert.

23 records · Page 2Linked to original sources

PubMed2003

Mechanisms of cancer prevention by tea constituents.

Consumption of tea (Camellia sinensis) has been suggested to prevent cancer, heart disease and other diseases. Animal studies have shown that tea and tea constituents inhibit carcinogenesis of the skin, lung, oral cavity, esophagus, stomach, liver, prostate and other organs. In some studies, the inhibition correlated with an increase in tumor cell apoptosis and a decrease in cell proliferation. Studies with human cancer cell lines have demonstrated that epigallocatechin-3-gallate (EGCG), a major tea polyphenol, inhibits mitogen-activated protein kinases, cyclin-dependent kinases, growth factor-related cell signaling, activation of activator protein 1 (AP-1) and nuclear factor kappaB (NFkappaB), topoisomerase I and matrix metalloproteinases as well as other potential targets. Although some studies report effects of EGCG at submicromolar levels, most experiments require concentrations of >10 or 20 micromol/L to demonstrate the effect. In humans, tea polyphenols undergo glucuronidation, sulfation, methylation, and ring fission. The peak plasma concentration of EGCG is approximately 1 micromol/L. The possible relevance of each of the proposed mechanisms to human cancer prevention is discussed in light of current bioavailability data for tea polyphenols and the potential limitations of animal models of carcinogenesis. Such discussion, it is hoped, will clarify some misunderstandings of cancer prevention by tea and stimulate new research efforts.

Animals↗

PubMed2003

Epigallocatechin-3-gallate is absorbed but extensively glucuronidated following oral administration to mice.

Epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea (Camellia sinensis), has shown cancer preventive activity in animal models. The bioavailability of EGCG in the most commonly used animal species, mice, is poorly understood. Moreover, the pharmacokinetic parameters of EGCG have not been reported previously in mice. Here we report that after administration of EGCG intravenously at 21.8 micro mol/kg or intragastrically at 163.8 micro mol/kg, the peak plasma levels of EGCG in male CF-1 mice were 2.7 +/- 0.7 and 0.28 +/- 0.08 micro mol/L, respectively. EGCG was present mainly (50-90%) as the glucuronide. The plasma bioavailability of EGCG after intragastric administration was higher than previously reported in rats (26.5 +/- 7.5% vs. 1.6 +/- 0.6%). The conjugated EGCG displayed a shorter t(1/2) (82.8-211.5 vs 804.9-1102.3 min) than unconjugated EGCG (P < 0.01, Student's t test). EGCG was present in the unconjugated form in the lung, prostate and other tissues at levels of 0.31-3.56 nmol/g after intravenous administration. Although intragastric administration resulted in lower levels in most tissues compared with intravenous administration (e.g., 0.006 +/- 0.004 vs. 2.66 +/- 1.0 nmol/g in the lung), the levels in the small intestine and colon were high at 45.2 +/- 13.5 and 7.86 +/- 2.4 nmol/g, respectively. This is the first report of the pharmacokinetic parameters of EGCG in mice. Such information provides a basis for understanding the bioavailability of EGCG in mice and should aid in understanding the cancer preventive activity of EGCG.

Administration, Oral↗

PubMed2002

Nordihydroguaiaretic acid: hepatotoxicity and detoxification in the mouse.

Larrea tridentata (Moc & Sess) Cov. (Zygophyllaceae) is an ethnobotanically important plant found in the American Southwest and northern Mexico. Although numerous beneficial effects have been attributed to this plant, several case reports have demonstrated high doses of Larrea-containing herbals induce hepatotoxicity and nephrotoxicity in humans. Nordihydriguaiaretic acid (NDGA) is a lignan found in high amounts (up to 10% by dry weight) in the leaves and twigs of L. tridentata. Previously, NDGA has been shown to induce cystic nephropathy in the rat, however, no reports have been made concerning this compound's hepatotoxic potential. Here, we report that intraperitoneal administration of NDGA is lethal in the mouse (LD(50)=75 mg/kg). Administration is associated with a time and dose-dependent increase in serum alanine aminotransferase levels, which suggest liver damage. Indeed, freshly isolated mouse hepatocytes are more sensitive to NDGA than human melanoma cells. Furthermore, we have identified glucuronidation as a potential detoxification mechanism for NDGA. Both mono and diglucuronide conjugates of NDGA are formed after intravenous dosing. The monoglucuronide is also formed after incubation of NDGA with human hepatic microsomes; suggesting that glucuronide conjugation is important in the metabolism of NDGA by humans. In summary, this report indicates that NDGA may contribute to the hepatotoxicity of L. tridentata and provides preliminary information on NDGA metabolism.

Alanine Transaminase↗

PubMedDate not supplied

Cancer chemopreventive activity and bioavailability of tea and tea polyphenols.

Consumption of tea (Camellia sinensis) has been associated with many health benefits including the prevention of cancer. Based on in vitro experiments, many mechanisms have been proposed to account for the cancer chemopreventive activity. The importance of some of these mechanisms in vivo remains in question due to an incomplete understanding of the bioavailability of the polyphenolic compounds in tea. In this article, the literature on the cancer chemopreventive activity of tea and the tea polyphenols is discussed as well as some of the possible mechanisms for this activity. Whereas studies in animal models and with cell lines have demonstrated cancer preventive activity, the epidemiological data remain mixed. This discrepancy may arise from several factors including lifestyle, correlation between animal models and humans, and differences in metabolism among individuals. Results on the bioavailability and biotransformation of the tea polyphenols help explain some of the differences. We hope this article will spark research efforts on some of the important questions regarding tea polyphenol bioavailability and cancer chemoprevention.

Animals↗

PubMedDate not supplied

Redox properties of tea polyphenols and related biological activities.

Plant polyphenolic compounds are known to be strong antioxidants. Because oxidative stress is believed to contribute to many acute and chronic diseases, these polyphenols have been postulated to have many beneficial health effects, such as the prevention of cancer and cardiovascular diseases. Indeed, some of these beneficial effects have been demonstrated in animal models and in some, but not all, epidemiological studies. Nevertheless, only some of these activities have been demonstrated to be associated with the antioxidative activities of polyphenols. In studies with cell lines in culture, some of the observed activities may be due to superoxide and hydrogen peroxide produced during the autooxidation of polyphenols. Such pro-oxidation-dependent reactions may not happen in tissues where the oxygen partial pressure is much lower than that in cell culture medium. This review will use the well-studied tea polyphenol, (-)-epigallocatechin-3-gallate, as an example to illustrate the redox properties of polyphenols and their influence on signaling pathways related to anti-cancer activities. Existing data suggest, however, that most of the relevant mechanisms of cancer prevention by tea polyphenols are not related to their redox properties, but are due to the direct binding of the polyphenol to target molecules, including the inhibition of selected protein kinases, matrix metalloproteinases, and DNA methyltransferases.

Animals↗