Biomedical subjects

R W Teel

Publications and source records attributed to R W Teel.

46 records · Page 3Linked to original sources

PubMedDate not supplied

Selective induction of apoptosis in human mammary cancer cells (MCF-7) by pycnogenol.

Breast cancer is the second leading cause of cancer death in women in the United States. The 1999 Cancer Facts and Figures, published by the American Cancer Society, estimates that almost 43,700 women and men will die of breast cancer in the United States. In this study, we compared the response of human breast cancer cells (MCF-7) and normal human mammary cells (MCF-10) to apoptosis in the presence of pycnogenol. Pycnogenol is a mixture of flavonoid compounds extracted from the bark of pine trees. MCF-7 and MCF-10 cells were plated out in culture dishes and grown in medium containing 0, 40, or 80 micrograms pycnogenol/ml culture medium. Cells were harvested at confluency, incubated with DAPI for 15 min and viewed microscopically for evidence of apoptosis. Apoptosis is detectable by morphology, chromatin condensation, nuclear DNA fragmentation, DNA strand breakage or apoptotic bodies. DAPI is a DNA-binding fluorescent dye used to visualize DNA fragmentation. Apoptosis, as detected by DAPI staining, was significantly higher in MCF-7 cells treated with pycnogenol than the untreated cells. The presence of pycnogenol did not significantly alter the number of apoptotic cells in MCF-10 samples. These results suggest that pycnogenol selectively induced death in human mammary cancer cells (MCF-7) and not in normal human mammary MCF-10 cells.

Antineoplastic Agents↗

PubMedDate not supplied

Effects of citrus phytochemicals on liver and lung cytochrome P450 activity and on the in vitro metabolism of the tobacco-specific nitrosamine NNK.

NNK is a potent environmental carcinogen to which both smokers and nonsmokers are exposed. The response to NNK may be affected by factors including nutrition. We investigated the effects of five citrus phytochemicals on the in vitro metabolism of the tobacco-specific nitrosamine NNK and on the dealkylation of methoxyresorufin (MROD) and pentoxyresorufin (PROD) in liver and lung microsomes of the Syrian golden hamster. In the NNK metabolism experiments in vitro incubations contained 3 microCi [5-H3] NNK, 0.5 mg microsomal protein and 0.5 mumole of the citrus phytochemical diosmin, naringin, naringenin, quercetin or rutin. In the dealkylation studies incubations contained 0.5 microM methoxyresorufin or pentoxyresorufin, 0.5 mg microsomal protein and 0.5 mumole of citrus phytochemical. The major NNK metabolism pathway in hamster liver microsomes was NNK-reduction while in lung microsomes it was alpha-hydroxylation. The alpha-hydroxylation pathway produces metabolic products that methylate and pyridyloxobutylate DNA. Naringenin, a metabolite of naringin, and quercetin were the most potent inhibitors of alpha-hydroxylation of NNK in both liver and lung microsomes. This inhibition correlated with a potent inhibition of MROD and PROD activity in liver but not in lung microsomes. The metabolic activation of NNK is associated with cytochrome P450 isoforms 1A1, 1A2, 2B1, 2D6 and 2E1. Our results suggest that naringenin and quercetin from citrus fruits inhibit the activity of cytochrome P450 (CYP) isoforms that activate NNK and may afford protection against NNK-induced carcinogenesis.

Animals↗

PubMedDate not supplied

Effects of citrus flavonoids on the mutagenicity of heterocyclic amines and on cytochrome P450 1A2 activity.

Heterocyclic amines (HCA's) are promutagens produced by high temperature cooking of meat products and are activated by cytochrome P450 (CYP) lA2. Using Aroclor 1254 induced rat liver S9 we tested four citrus flavonoids diosmin, naringenin, naringin and rutin for their effects on the mutagenicity of HCA's MeIQx, Glu-P-1*, IQ and PhIP in Salmonella typhimurium TA98. The effects of the citrus flavonoids on CYPlA2 activity was determined by measuring demethylation of methoxyresorufin (MROD). MeIQx induced mutagenesis in S. typhimurium was significantly inhibited by all four flavonoids in a concentration dependent manner at 0.25, 0.5 and 1.0 mumole. Glu-P-1 induced mutagenesis was inhibited by rutin and naringenin. IQ induced mutagenesis was significantly inhibited by each flavonoid except diosmin at all three doses. With the exception of diosmin and naringin at 0.25 mumole all four flavonoids at all three doses significantly inhibited PhlP induced mutagenesis. The inhibition of MROD activity by the citrus flavonoids correlated best with the inhibition of MeIQx induced mutagenesis but also correlated with the inhibition of IQ induced mutagenesis except for diosmin and with the inhibition of PhlP induced mutagenesis except for the 0.25 mumole dose of diosmin and naringin. Our data suggest a chemopreventive potential for diosmin, naringin, naringenin and rutin towards CYPlA2 mediated mutagenesis of HCA's.

Animals↗

PubMedDate not supplied

Effects of plant-derived phenols on rat liver cytochrome P450 2B1 activity.

Dietary constituents contain a variety of compounds that are known to modulate liver enzyme activity. In this report, the plant-derived phenols catechin, chlorogenic acid, diosmin, epigallo-catechin gallate (EGCG), naringenin, quercetin and resveratrol were studied for their effects on the activity of cytochrome P450 2B1 in liver microsomes from 6- and 20-month male Fisher F344 rats. The compounds at two concentrations (0.1 and 0.25 mM) were incubated with 0.2 mg liver microsomal protein and 50 microM 7-ethoxy-4-trifluoromethyl coumarin (EFC). O-deethylation of EFC to the fluorescence product 7-hydroxy-4-trifluoromethyl coumarin (HFC) is catalyzed by CYP450 2B1. EGCG, naringenin, quercetin and resveratrol inhibited the in vitro O-deethylation of EFC in liver microsomes from both 6- and 20-month rats. Quercetin was the most effective inhibitor. Catechin inhibited the in vitro O-deethylation of EFC only in microsomes from 6-month-old rats whereas diosmin inhibited the reaction only in microsomes from 20-month-old rats. Chlorogenic acid inhibited the in vitro O-deethylation of EFC in microsomes from both age groups at the 0.25 mM concentration only. These results suggest that plant phenols have varied effects on liver microsomal cytochrome P450 2B1 activity that may be influenced by the age of the animal.

Alkylation↗

PubMedDate not supplied

Effects of different inducers of cytochrome P450 on the mutagenesis of the tobacco-specific nitrosamine 4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanone (NNK) in Salmonella typhimurium TA1535.

The effects of six inducers of isoenzymes of cytochrome P450 on the mutagenicity of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in Salmonella typhimurium strain TA1535 by hamster liver S9 and microsomes were investigated. Comparisons of the effects of dimethylsulfoxide (DMSO) as solvent for NNK were also made. The inducing agents were Aroclor 1254 (AROC), 3-methylcholanthrene (MC), phenobarbital (PB), dexamethasone (DXM), ethanol (ETOH) and isosafrol (ISF). The number of histidine-independent colonies induced by NNK in saline mediated by S9 from the inducing agents was as follows: ISF = AROC greater than PB greater than MC greater than DXM greater than ETOH. AROC-induced microsomes produced the most revertants by NNK (saline) greater than MC greater than PB = DXM and ISF greater than ETOH. The number of revertant colonies induced by NNK in DMSO was significantly less than that by NNK in saline for both hamster liver S9 and microsomes irrespective of the inducing agent. The greatest inhibitory effect of DMSO was observed with ISF-induced S9.

Animals↗

PubMedDate not supplied

Binding of aflatoxin B1 to DNA inhibited by ajoene and diallyl sulfide.

Components of garlic have been shown to inhibit a variety of tumors induced by chemical carcinogens. In this study we determined the effects of ajoene and diallyl sulfide (DAS), two organosulfur compounds of garlic, on the metabolism and DNA binding of aflatoxin B1 (AFB1) using rat liver 9000Xg supernatant as the metabolic activation system. Organosoluble and water-soluble metabolites of [3H]AFB1 were isolated by reverse-phase high performance liquid chromatography (HPLC). The effects of ajoene and DAS on glutathione-S-transferase (GST) were determined using 1-chloro-2,4-dinitrobenzene as the substrate. Ajoene and DAS at 100 mg/ml inhibited [3H]AFB1 binding to calf thymus DNA and adduct formation. They decreased the formation of both organosoluble and water-soluble metabolites of [3H]AFB1. Neither compound significantly affected GST activity. These results indicate that ajoene and DAS affected AFB1 metabolism and DNA binding by inhibiting phase I enzymes and may therefore be considered as potential cancer chemopreventive agents.

Aflatoxin B1↗

PubMedDate not supplied

Effects of isothiocyanates on the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene by hamster and rat liver microsomes.

Benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC) strongly inhibited the N-pyridine oxidation and alpha-carbon hydroxylation pathways of the in vitro metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by Syrian golden hamster liver microsomes from saline-injected (noninduced) animals. PEITC was more potent than BITC. NNK-reduction was enhanced by both isothiocyanates. Both N-oxidation and alpha-hydroxylation activities were several-fold greater in hamster liver microsomes compared with F344 rat liver microsomes. Consequently, the inhibitory effect of BITC and PEITC on rat liver microsomes (noninduced) was not as pronounced. NNK-reduction in rat liver microsomes was not significantly different from hamster and was not enhanced by BITC and PEITC. Neither BITC nor PEITC had a strong inhibitory effect on the in vitro metabolism of benzo[a]pyrene (BaP) by either hamster or F344 rat liver microsomes from beta-naphthoflavone treated animals. The extent of BaP metabolism was similar for the two microsome groups. Since the metabolism of NNK and BaP depends upon cytochrome P450-mediated reactions that may utilize different isozymes of cytochrome P450, our data suggest that BITC and PEITC may inhibit the activity of some isozymes and not others. Our results also indicate that the inhibition of the metabolism of NNK by isothiocyanates as previously described for the mouse and rat can now be extended to include the hamster as well.

Animals↗

PubMedDate not supplied

Inhibition of liver microsomal cytochrome P450 activity and metabolism of the tobacco-specific nitrosamine NNK by capsaicin and ellagic acid.

The tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone (NNK), present in tobacco and tobacco smoke, is metabolically activated by microsomal enzymes. In this study, we examined the effect of capsaicin and ellagic acid on the in vitro metabolism of NNK by hamster and rat liver microsomes. Capsaicin is the principal component of Capsicum fruits used widely throughout the world as a food additive. Ellagic acid, with reported anticarcinogenic properties, is found in various soft fruits and nuts. Both capsaicin and ellagic acid inhibited the major pathways of NNK-reduction, N-pyridine oxidation and a-hydroxylation by hamster liver microsomes. Capsaicin inhibited NNK-reduction and a-hydroxylation and ellagic acid inhibited N-oxidation and a-hydroxylation by rat liver microsomes. The effects of capsaicin and ellagic acid on isozymes of cytochrome P450 were observed in the hydroxylation reactions of the metabolism of the steroid hormone testosterone. Results of these experiments indicated that both capsaicin and ellagic acid strongly inhibited the constitutive enzymes CYP 2A2, 3A1, 2C11, 2B1, 2B2 and 2C6. This study suggests that capsaicin and ellagic acid, as naturally occurring dietary constituents, possess antimutagenic and anticarcinogenic properties through the inhibition of xenobiotic metabolizing enzymes.

Animals↗

PubMedDate not supplied

Effects of isothiocyanates on cytochrome P-450 1A1 and 1A2 activity and on the mutagenicity of heterocyclic amines.

In this study we investigated the effects of phenyl isothiocyanate (PITC), benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC) and phenylpropyl isothiocyanate (PPITC) on the mutagenicity of five heterocyclic amines, IQ, MeiQx, Trp-P-2, Glu-P-2 and PhIP in Salmonella typhimurium strain TA 98 in the presence of liver microsomes from male Syrian golden hamsters. In addition, the effects of these isothiocyanates on cytochrome P-450 1A1 and cytochrome P-450 1A2 activities were determined by measuring the deethylation and the demethylation of ethoxyresorufin (EROD) and methoxyresorufin (MROD) respectively. With the exception of Trp-P-2, all four isothiocyanates significantly inhibited HCA-induced mutagenesis in TA 98 at concentrations of 0.05 and 0.1 mumoles/plate. BITC was the only isothiocyanate tested that showed a dose-dependent inhibition of Trp-P-2-induced mutagenesis. These four isothiocyanates showed a dose-dependent inhibition of EROD activity and, with the exception, of BITC, of MROD activity also. This indicates that the inhibition of HCA-induced mutagenesis correlates with the inhibition of cytochrome P-450 1A1 and 1A2. These P450s are known to metabolically activate HCAs. The inhibitory effects of the isothiocyanates were greater toward HCA-induced mutagenesis in TA 98 than toward EROD and MROD activity. This indicates that the antimutagenic effects of PITC, BITC, PEITC and PPITC on HCA-induced mutagenesis in Salmonella typhimurium TA 98 involves more than the inhibition of cytochrome P-450 1A1 and 1A2 activity in hamster liver microsomes.

Animals↗

PubMedDate not supplied

Effects of orally administered capsaicin, the principal component of capsicum fruits, on the in vitro metabolism of the tobacco-specific nitrosamine NNK in hamster lung and liver microsomes.

Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is the principal component in Capsicum fruits consumed worldwide as a food additive. Capsaicin is known for its hot, pungent qualities. The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is viewed as an important etiological factor in the causation of human lung cancer. In our study, a single oral dose of capsaicin administered by oral gavage at 2 mg/kg and 10 mg/kg body weight to male Syrian golden hamsters altered the in vitro metabolism of NNK by liver and lung microsomes. The most significant effect was on the inhibition of alpha-carbon hydroxylation. The orally administered capsaicin inhibited the formation of keto aldehyde (methylating pathway) and the formation of keto alcohol (pyridyloxobutylating pathway) in lung microsomes except for microsomes from animals receiving 10 mg/kg capsaicin 24 h post-treatment. In contrast, capsaicin inhibited only the methylating pathway in liver microsomal metabolism of NNK. This effect persisted at 24 h post-treatment. Since it is reported that the pyridyloxobutylating pathway enhances the effects of the more damaging methylating pathway in the metabolism of NNK (reference 25), our results suggest that any potentially chemopreventive action of orally administered capsaicin may be greater toward NNK-induced lung tumorigenesis than toward NNK-induced liver tumorigenesis.

Administration, Oral↗