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Numerous laboratory studies reveal that various naturally occurring dietary substances can modify the patho-physiological process of various metabolic disorders and can be an effective preventive strategy for various diseases, including cancer. Indian Neem tree, Azadirachta indica A. Juss. (family: Meliaceae), contains at least 35 biologically active principles and is widely grown all over the tropics. The effect of two different doses (250 and 500 mg per kilogram body weight) of 80% ethanolic extract of the leaves of Azadirachta indica were examined on drug metabolizing Phase-I and Phase-II enzymes, antioxidant enzymes, glutathione content, lactate dehydrogenase, and lipid peroxidation in the liver of 7-week-old Swiss albino mice. Also anticarcinogenic potential of Azadirachta indica leaf extract was studied adopting protocol of benzo(a)pyrene-induced fore-stomach and 7,12-dimethyl benz(a)anthracene (DMBA)-induced skin papillomagenesis. Our primary findings reveal its potential to induce only the Phase-II enzyme activity associated mainly with carcinogen detoxification in liver of mice. The hepatic glutathione S-transferase (P < 0.005) and DT-diaphorase specific activities (P < 0.01) were elevated above basal level. With reference to antioxidant enzymes the investigated doses were effective in increasing the hepatic glutathione reductase (GR), glutathione peroxidase (GPX), superoxide dismutase (SOD) and catalase (CAT) activities significantly (from P < 0.005 to P < 0.001). Reduced glutathione measured as non-protein sulphydryl was found to be significantly elevated in liver (P < 0.005) and in extrahepatic organs (from P < 0.005 to P < 0.001) examined in our study. Glutathione S-transferase (GST) and DT-diaphorase (DTD) showed a dose-dependent increase in extrahepatic organs. Chemopreventive response was measured by the average number of papillomas per mouse, as well as percentage of tumor-bearing animals. There was a significant inhibition of tumor burden, in both the tumor model system studied (from P < 0.005 to P < 0.001). Tumor incidence was also reduced by both the doses of Azadirachta indica extract., (Copyright 2003 Elsevier Ireland Ltd.)

Basil or sweet basil (Ocimum basilicum) is cultivated throughout India and is known for its medicinal value. The effects of doses of 200 and 400 mg/kg body weight of hydroalcoholic extract (80% ethanol, 20% water) of the fresh leaves of Ocimum basilicum on xenobiotic metabolizing Phase I and Phase II enzymes, antioxidant enzymes, Glutathione content, Lactate dehydrogenase and lipid peroxidation in the liver of 8-9 weeks old Swiss albino mice were examined. Furthermore, the anticarcinogenic potential of basil leaf extract was studied, using the model of Benzo(a)pyrene-induced forestomach and 7,12 dimethyl benz(a)anthracene (DMBA)-initiated skin papillomagenesis. The hepatic glutathione S-transferase and DT-diaphorase specific activities were elevated above basal level by basil leaf treatment (from p < 0.005 to p < 0.001). Basil leaf extract was very effective in elevating antioxidant enzyme response by increasing significantly the hepatic glutathione reductase (GR) (p < 0.005), superoxide dismutase (SOD) (p < 0.05), and catalase activities (p < 0.005). Reduced glutathione (GSH), the major intracellular antioxidant, showed a significant elevation in the liver (p < 0.005) and also in all the extrahepatic organs (from p < 0.05 to p < 0.005). In the forestomach, kidney and lung, glutathione S-transferase and DT-diaphorase levels were augmented significantly, varying from p < 0.01 to p < 0.001. There were significant decreases in lipid peroxidation and lactate dehydrogenase activity. Chemopreventive response was evident from the reduced tumor burden (the average number of papillomas/mouse, p < 0.005 to p < 0.001), as well as from the reduced percentage of tumor bearing-animals. Basil leaf, as deduced from the results, augmented mainly the Phase II enzyme activity that is associated with detoxification of xenobiotics, while inhibiting the Phase I enzyme activity. There was an induction in antioxidant level that correlates with the significant reduction of lipid peroxidation and lactate dehydrogenase formation. Moreover, Basil leaf extract was highly effective in inhibiting carcinogen-induced tumor incidence in both the tumor models at peri-initiational level.

The present study was conducted to ascertain the modulatory influences of Ferula asafoetida L. (asafoetida, flavoring agent) on the mammary epithelial tissue differentiation, hepatic drug metabolizing enzymes, antioxidant profiles and N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis in Sprague-Dawley rats. Feeding with two doses of asafoetida (1.25 and 2.5% w/w in diet) showed a remarkable increase in the development and differentiation of ducts/ductules (p < 0.01-0.005), lobules (p < 0.005) and a decrease in terminal end buds (p < 0.05-0.005) as compared to both normal and MNU-treated control animals. To assess the biochemical parameters, effect of asafoetida on drug-metabolizing enzymes was evaluated in the liver of rats. Asafoetida treatment significantly reduced (p < 0.05) the levels of cytochrome P450 and b5. There was an enhancement in the activities of glutathione S-transferase (p < 0.05-0.005), DT-diaphorase (p < 0.05-0.01), superoxide dismutase (p < 0.01-0.005) and catalase (p < 0.05-0.005) and in the level of reduced glutathione (p < 0.05-0.005), followed by asafoetida treatment. Also, asafoetida significantly restored the level of antioxidant system, depleted by MNU-treatment. The strengthening of antioxidant system by the lower and higher doses of asafoetida in the presence and absence of MNU was further substantiated by a significant inhibition (p < 0.005) in lipid peroxidation as measured by thiobarbituric acid-reactive substances (TBARS) in the liver of rat. Further, in long-term animal studies, where MNU was used to induce mammary carcinogenesis, asafoetida treatment resulted in a significant reduction in the multiplicity (p < 0.001) and size of palpable mammary tumors (p < 0.005-0.001) and a delay in mean latency period of tumor appearance (p < 0.005). Together, these findings indicate the chemopreventive potential of asafoetida against MNU-induced mammary carcinogenesis. Thus, asafoetida needs further investigation with regard to identification and characterization of its active principle(s) and mechanism of action, for this compound to be developed as a potential chemopreventive agent for human cancers.

Henna leaf (Lawsonia inermis), commonly known as Mehndi is cultivated throughout India and is a very popular natural dye to color hand and hair. It is an integral part of indigenous culture, and is also known for its medicinal value. The effect of 200 and 400 mg/kg body weight of 80% ethanolic extract of the fresh leaves of Lawsonia inermis were examined on drug metabolizing phase-I and phase-II enzymes, antioxidant enzymes, glutathione content, lactate dehydrogenase and lipid peroxidation in the liver of 7 weeks old Swiss albino mice. Also anticarcinogenic potential of Henna leaf extract was studied adopting the protocol of benzo(a)pyrene induced forestomach and 7,12 dimethylbenz(a)anthracene (DMBA)-initiated and croton oil-promoted skin papillomagenesis. Our primary findings reveal the 'duel-acting' nature of henna leaf as deduced from its potential to induce only the phase-II enzyme activity, associated mainly with carcinogen detoxification in liver of mice and inhibit the phase I enzyme activities. The hepatic glutathione S-transferase and DT-diaphorase specific activities were elevated above basal (p < 0.005) level by Lawsonia inermis extract treatment. With reference to antioxidant enzymes the investigated doses were effective in increasing the hepatic glutathione reductase (GR), superoxide dismutase (SOD) and catalase activities significantly (from p < 0.05 to p < 0.005) at both the dose levels. Reduced glutathione (GSH) measured as non-protein sulphydryl was found to be significantly elevated in liver (p < 0.005) and in all the extrahepatic organs studied (from p < 0.05 to p < 0.005). Among the extrahepatic organs examined (forestomach, kidney and lung) glutathione S-transferase and DT-diaphorase level were increased in a dose independent manner (from p < 0.05 to p < 0.005). Chemopreventive response was measured by the average number of papillomas per mouse (tumor burden) as well as percentage of tumor bearing animals and tumor multiplicity. There was a significant inhibition of tumor burden in both the tumor model systems studied (from p < 0.01 to p < 0.001). Tumor incidence was also reduced by both the doses used in our experiment in both the model systems.

Lately, a strong correlation has been established between diet and cancer. For ages, cumin has been a part of the diet. It is a popular spice regularly used as a flavoring agent in a number of ethnic cousins. In the present study, cancer chemopreventive potentials of different doses of a cumin seed-mixed diet were evaluated against benzo(a)pyrene [B(a)P]-induced forestomach tumorigenesis and 3-methylcholanthrene (MCA)-induced uterine cervix tumorigenesis. Results showed a significant inhibition of stomach tumor burden (tumors per mouse) by cumin. Tumor burden was 7.33 +/- 2.10 in the B(a)P-treated control group, whereas it reduced to 3.10 +/- 0.57 (P < 0.001) by a 2.5% dose and 3.11 +/- 0.60 (P <0.001) by a 5% dose of cumin seeds. Cervical carcinoma incidence, compared with the MCA-treated control group (66.67%), reduced to 27.27% (P < 0.05) by a diet of 5% cumin seeds and to 12.50% (P < 0.05) by a diet of 7.5% cumin seeds. The effect of 2.5 and 5% cumin seed-mixed diets was also examined on carcinogen/xenobiotic metabolizing phase I and phase II enzymes, antioxidant enzymes, glutathione content, lactate dehydrogenase (LDH), and lipid peroxidation in the liver of Swiss albino mice. Levels of cytochrome P-450 (cyt P-450) and cytochrome b5 (cyt b(5)) were significantly augmented (P < 0.05) by the 2.5% dose of cumin seed diet. The levels of cyt P-450 reductase and cyt b(5) reductase were increased (significance level being from P < 0.05 to P < 0.01) by both doses of cumin. Among the phase II enzymes, glutathione S-transferase specific activity increased (P < 0.005) by the 5% dose, whereas that of DT-diaphorase increased significantly (P < 0.05) by both doses used (2.5 and 5%). In the antioxidant system, significant elevation of the specific activities of superoxide dismutase (P < 0.01) and catalase (P < 0.05) was observed with the 5% dose of cumin. The activities of glutathione peroxidase and glutathione reductase remained unaltered by both doses of cumin. The level of reduced glutathione measured as nonprotein sulfhydryl content was elevated (significance level being from P < 0.05 to P < 0.01) by both doses of cumin. Lipid peroxidation measured as formation of MDA production showed significant inhibition (P < 0.05 to P < 0.01) by both doses of cumin. LDH activity remained unaltered by both doses of cumin. The results strongly suggest the cancer chemopreventive potentials of cumin seed and could be attributed to its ability to modulate carcinogen metabolism.

The effects of two doses (50 and 100 mg/kg body wt/day for 14 days) of an 80% hydroalcohol extract of Andrographis paniculata and butylated hydroxyanisole (BHA) were examined on drug metabolizing enzymes, antioxidant enzymes, glutathione content, lactate dehydrogenase (LDH) and lipid peroxidation in the liver of Swiss albino mice (6-8 weeks old). The effect of the extract and BHA were also examined on lung, kidney and forestomach for the activities of glutathione S-transferase (GST), DT-diaphorase (DTD), superoxide dismutase (SOD) and catalase. A significant increase in the levels of acid soluble sulphydryl (-SH) content, cytochrome P450, cytochrome P450 reductase, cytochrome b5 reductase, GST, DTD and SOD were observed at both dose levels of extract treatment while catalase, glutathione peroxidase and glutathione reductase (GR) showed significant increases only at the higher dose in the liver. Both Andrographis treated groups showed a significant decrease in activity of LDH and malondialdehyde (MDA) formation. BHA treated mice showed a significant increase in the levels of cytochrome b(5), GST, DTD, -SH content, GR and catalase in liver; while LDH and MDA levels were reduced significantly compared with their control values. In the lung, SOD, catalase and DTD, in the kidney catalase, DTD and GST, and in the forestomach SOD and DTD showed a significant increase at both dose levels of treatment. In BHA treated mice GST, DTD and catalase were significantly induced in the lung and along with these enzymes SOD was also induced in the kidney. In the case of the forestomach of BHA treated mice GST, DTD and SOD were enhanced significantly. These findings indicate the chemopreventive potential of Andrographis paniculata against chemotoxicity including carcinogenicity., (Copyright 2001 John Wiley & Sons, Ltd.)

The effect of two different doses (50 and 100 mg/kg body wt/day for 14 days) of 80% ethanolic extract of the leaves of Adhatoda vesica were examined on drug metabolizing phase I and phase II enzymes, antioxidant enzymes, glutathione content, lactate dehydrogenase and lipid peroxidation in the liver of 8 weeks old Swiss albino mice. The modulatory effect of the extract was also examined on extra-hepatic organs viz. lung, kidney and forestomach for the activities of glutathione S-transferase, DT-diaphorase, superoxide dismutase and catalase. Significant increase in the activities of acid soluble sulfhydryl (-SH) content, cytochrome P450, NADPH-cytochrome P450 reductase, cytochrome b5, NADH-cytochrome b5 reductase, glutathione S-transferase (GST), DT-diaphorase (DTD), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) were observed in the liver at both dose levels of treatments. Adhatoda vesica acted as bifunctional inducer since it induced both phase I and phase II enzyme systems. Both the treated groups showed significant decrease in malondialdehyde (MDA) formation in liver, suggesting its role in protection against prooxidant induced membrane damage. The cytosolic protein was significantly inhibited at both the dose levels of treatment indicating the possibility of its involvement in the inhibition of protein synthesis. BHA has significantly induced the activities of GR and GSH in the present study. The extract was effective in inducing GST and DTD in lung and forestomach, and SOD and CAT in kidney. Thus, besides liver, other organs viz., lung, kidney and forestomach were also stimulated by Adhatoda, to increase the potential of the machinery associated with the detoxification of xenobiotic compounds. But, liver and lung showed a more consistent induction. Since the study of induction of the phase I and phase II enzymes is considered to be a reliable marker for evaluating the chemopreventive efficacy of a particular compound, these findings are suggestive of the possible chemopreventive role played by Adhatoda leaf extract.

The effect of two doses (30 microl and 60 microl/day/mice daily for 14 days) of the fresh leaf pulp extract of Aloe vera was examined on carcinogen-metabolizing phase-I and phase-II enzymes, antioxidant enzymes, glutathione content, lactate dehydrogenase and lipid peroxidation in the liver of mice. The modulatory effect of the pulp extract was also examined on extrahepatic organs (lung, kidney and forestomach) for the activities of glutathione S-transferase, DT-diophorase, superoxide dismutase and catalase. The positive control mice were treated with butylated hydroxyanisole (BHA). Significant increases in the levels of acid soluble sulfhydryl (-SH) content, NADPH-cytochrome P450 reductase, NADH-cytochrome b5 reductase, glutathione S-transferase (GST), DT-diaphorase (DTD), superoxide dismutase (SOD), catalase, glutathione peroxidase (GPX) and glutathione reductase (GR) were observed in the liver. Aloe vera significantly reduced the levels of cytochrome P450 and cytochrome b5. Thus, Aloe vera is clearly an inducer of phase-II enzyme system. Treatment with both doses of Aloe caused a decrease in malondialdehyde (MDA) formation and the activity of lactate dehydrogenase in the liver, suggesting its role in protection against prooxidant-induced membrane and cellular damage. The microsomal and cytosolic protein was significantly enhanced by Aloe vera, indicating the possibility of its involvement in the induction of protein synthesis. BHA, an antioxidant compound, provided the authenticity of our assay protocol and response of animals against modulator. The pulp extract was effective in inducing GST, DTD, SOD and catalase as measured in extrahepatic organs. Thus, besides liver, other organs (lung, kidney and forestomach) were also influenced favorably by Aloe vera in order to detoxify reactive metabolites, including chemical carcinogens and drugs.

The modulatory potential of Spirulina fusiformis was observed on the hepatic and extrahepatic carcinogen metabolizing enzymes in Swiss albino mice at a dose of 800 mg/kg b.w. given orally. A significant reduction in the hepatic cytochrome P-450 content was observed in the group treated with Spirulina in comparison with the control group. The hepatic glutathione S-transferase activity was induced significantly by Spirulina treatment. There was no change in the extrahepatic glutathione S-transferase activity after the animals were fed with Spirulina.

The present study deals with the chemopreventive action of the food-seasoning spices mixture Garam masala on dimethylbenz[a]anthracene (DMBA)-induced translactational and transplacental carcinogenesis in mice. When pregnant mice were given 10 and 30 mg of Garam masala per day from Days 13-19 of gestation in addition to DMBA (5 mg/day) on Days 15-17 of gestation, the multiple-site tumor incidence declined significantly from control level of 62% to 19% and 10%, respectively, in F1 progeny. Furthermore the mean numbers of tumors per effective F1 mouse were reduced from the control value of 1.27 to 0.64 at the lower dose level (10 mg) and 0.23 at the higher dose level (30 mg) of Garam masala. Likewise, when lactating mice were given Garam masala at 10 and 30 mg/day for the first 15 days of lactation in addition to DMBA (3 mg/day) on Days 3, 6, 9, 12, and 15 of lactation, the multiple-site tumor incidence was reduced significantly from control level of 66% to 23% and 14%, respectively, in F1 progeny. The mean numbers of tumors per effective F1 mouse declined from control value of 1.43 to 0.46 at the lower dose and 0.25 at the higher dose of Garam masala. Further studies are required to analyze the nature of active chemical components and the manner in which they achieve chemoprevention in these complex model systems.

The present study examines the possible transfer of the active principle(s) of mace (aril of the plant Myristica fragrans) through the transmammary route and its ability to modulate hepatic xenobiotic metabolizing enzymes in the F1 progeny of mice. An aqueous suspension of mace at the dose levels of 0.025 or 0.1 g/animal/day was administered by oral gavage to dams from day 1 of lactation and continued daily for 14 or 21 days. Dams receiving mace treatment and their F1 pups showed significantly elevated hepatic sulfhydryl content, glutathione S-transferase and glutathione reductase activities and cytochrome b5 content. Hepatic cytochrome P450 content decreased in dams (P < 0.05) receiving the lower mace dose for 21 days and the F1 pups (P < 0.001), but increased in dams receiving the higher dose for both time periods (P < 0.001) and the lower dose for 14 days (P < 0.05). Only the 14-day-old pups of dams receiving either mace dose showed significantly elevated (P < 0.001) levels of hepatic glutathione peroxidase.

The present study evaluates the possible modulatory influence of ascorbic acid (AA) on (methylcholanthrene) MCA-induced cervical carcinogenesis in mice. Ascorbic acid was given daily for different durations in drinking water at the dose level of 2 mg/ml. In animals that received no modulator, placement of cotton threads impregnated with beeswax containing -600 micrograms of MCA for 16 weeks yielded 76.1% carcinomas in the uterine cervix. Administration of AA for the entire period of 16 weeks resulted in the reduction of MCA-induced cervical carcinomas to 33.3%. AA was capable of reducing cervical cancer incidence to 33.3% even when it was given for only 6 weeks following MCA-thread insertion into the uterine cervix. However, when it was given for a period of 10 weeks after 6 weeks of MCA-thread insertion the carcinoma incidence was as high as 66.6%. Results of the present study demonstrate that AA, especially when given during the initiational phase, significantly inhibits MCA-induced cervical carcinogenesis in mice.

The present paper reports the modifying potential of areca nut (Areca catechu), an ingredient of the habitual masticatory betel quid, on the induction of the hepatic detoxification system in mice by mace (the aril of nutmeg, Myristica fragrans) a known chemopreventor of chemically induced carcinogenesis. The modulatory effect of areca nut was assessed by determining the levels of enzymes of the hepatic detoxification system, such as glutathione S-transferase (GST), cytochrome b5 and cytochrome P-450, and the content of acid-soluble sulphhydryl (-SH). Mice were fed either control diet or diet containing 0.25, 0.5 or 1% areca nut for 45 days. During the last 10 days the diet was supplemented with 0.5 or 1% mace. At 0.5 and 1% in the diet, areca nut decreased mace-induced increases in hepatic GST and -SH levels and elevated further increases in the levels of cytochrome b5 and cytochrome P-450.

The placement of cotton thread impregnated with beeswax containing methylcholanthrene (MCA, approximately 600 micrograms) inside the canal of the uterine cervix of virgin, adult mice results in the emergence of precancerous and cancerous lesions in the cervical epithelium. Employing this experimental carcinogenesis model system, the present study evaluates the chemopreventive action of selenium on the incidences of precancerous and cancerous lesions in the cervical epithelium. When selenium was administered through drinking water at the dose level of 1 ppm for 1 week before and 12 weeks following carcinogen thread insertion, the cervical carcinoma incidence, as compared to that in control mice (72%), was 37%. This decline in the incidence of carcinoma was significant (p less than 0.05). The incidences of hyperplasia and dysplasia show a decreasing trend with selenium treatment in MCA-thread-inserted animals.