Chemopreventive effects of diosmin and hesperidin on N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine‐induced urinary‐bladder carcinogenesis in male ICR mice

Yang, Muzheng; Tanaka, Takuji; Hirose, Yoshio; Deguchi, Takashi; Mori, Hideki; Kawada, Yukimichi

doi:10.1002/(sici)1097-0215(19971127)73:5<719::aid-ijc18>3.3.co;2-v

Cited by 48 publications

(57 citation statements)

References 4 publications

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“…In mice urinary bladder carcinogenesis, other chemopreventive agents were proved to reduce the cell proliferation of BBN-induced various bladder lesions. 37,44 We also analyzed cyclin D1, cell cycle regulatory proteins control proliferation and cell cycle progression. Expression of cyclin D1 is believed to lead to progression through the G1-S cell cycle checkpoint, and both experimental and pathological evidence suggest that overexpression of this protein may increase the risk of several cancers, including transition cell carcinoma of the bladder.…”

Section: Discussionmentioning

confidence: 99%

“…Because the inhibitory action of ITC has been attributed to their ability to modulate xenobiotic-metabolizing enzymes (e.g., cytochrome P-450) that are required for the activation of many carcinogens or to induce Phase II detoxifying enzymes. 44,[63][64][65] . One possibility is that cytochrome P-450 are critical targets in inhibition of the chemical-induced tumorigenesis by ITC, the distinct patterns of P-450 isozymes for carcinogen activation in rats and mice may be partially responsible for the differences observed.…”

Section: Discussionmentioning

confidence: 99%

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Suppressive effect of 1,4-phenylene diisothiocyanate onN-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice

Sugie¹,

Vinh²,

Rahman³

et al. 2005

Int. J. Cancer

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The modifying effects of dietary administration of 1,4-phenylene diisothiocyanate (DITC) on N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced urinary bladder carcinogenesis during the initiation and post-initiation phases were examined in male ICR mice. Five-week-old animals were divided into 5 groups. Groups 1-3 were given BBN (500 ppm) in drinking water for 6 weeks starting at age 6 week. Mice in Group 2 were given the diet containing 100 ppm DITC for 8 weeks during the initiation phase, starting 1 week before BBN exposure. Animals in Group 3 were fed the experimental diet for 24 weeks during the post-initiation phase starting 1 week after the cessation of BBN exposure. Mice in Group 4 were given only the diet containing the test compound, and those in Group 5 were given the basal diet alone throughout the experiment (32 weeks). The frequency of bladder lesions, neoplasms, dysplasia and hyperplasia, was analyzed histopathologically. The cell-proliferation activity estimated by the 5-bromodeoxyuridine labeling index (BrdU-LI), and cell cycle progression by counting cyclin D1-positive cell ratios were compared among the groups using immunohistochemistry. Administration of DITC in the initiation phase reduced significantly the incidence of urinary bladder carcinoma and dysplasia. The frequencies of any lesions of urinary bladder were not reduced by DITC in post-initiation phase. Dietary exposure of this agent in initiation phase reduced significantly both BrdU-LI and cyclin D1-positive cell ratios in any bladder lesions. Administration of DITC in post-initiation phase also significantly reduced BrdU-LI in bladder neoplasms and hyperplasia and cyclin D1-positive cell ratios in urinary bladder carcinoma as well as dysplasia. These results suggest that dietary DITC could be a preventive agent against BBNinduced bladder carcinogenesis in mice when fed during the initiation phase. ' 2005 Wiley-Liss, Inc.Key words: chemoprevention; DITC; BBN; cyclin D1; BrdU labeling index; urinary bladder carcinogenesis Epidemiologic studies suggest that the consumption of green and yellow vegetables has an inverse relationship with cancer risk. [1][2][3][4][5][6][7] Organosulfur compounds that are present abundantly in a group of cruciferous vegetables or allium species have been shown to possess cancer chemopreventive properties. [8][9][10] Especially, isothiocyanates (ITC) are versatile chemopreventive agents in many animal systems.Cancer prevention studies of our group have demonstrated that benzyl isothiocyanate (BITC) inhibit methylazoxymethanol (MAM)-acetate induced intestinal carcinogenesis and diethylnitrosamine (DEN) induced hepatocarcinogenesis in rats, and sinigrin reduced 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis and DEN-induced hepatocarcinogenesis.11-14 We also found that BITC reduced not only unscheduled DNA synthesis (UDS) but also replicative DNA synthesis (RDS), induced by some genotoxic carcinogens, e.g., 2-acetylaminofluorene (AAF), MAM acetate, 9,10-dimethyl-1,2-benzanthracene (DMBA), and DEN....

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Suppressive effect of 1,4-phenylene diisothiocyanate onN-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice

Sugie¹,

Vinh²,

Rahman³

et al. 2005

Int. J. Cancer

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“…These effects may be of benefit for the prevention of cardiovascular diseases. Furthermore, hesperidin has been reported to protect animals against chemically induced cancers of colon, bladder, skin, and oesophagus Yang et al, 1997;Berkarda et al, 1998). The mechanisms involved are still unknown.…”

Section: Introductionmentioning

confidence: 99%

Bioavailability in humans of the flavanones hesperidin and narirutin after the ingestion of two doses of orange juice

Manach¹,

Morand²,

et al. 2003

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Objective: Flavanones are polyphenols specific of citrus fruits, where they are present in high amounts. Although citrus fruits and juices are widely consumed in the world, little information has been published on flavanone bioavailability in humans. The aim of the present study was to determine the nature of the circulating metabolites, the plasma kinetics and the urinary excretion patterns of the flavanones, hesperidin and narirutin. Design: After an overnight fast, five healthy volunteers ingested 0.5 or 1 l of a commercial orange juice providing 444 mg=l hesperidin and 96.4 mg=l narirutin, together with a polyphenol-free breakfast. Blood was sampled at 10 different timepoints over a 24 h period. Urine was collected for 48 h, in five fractions. Results: Flavanones metabolites appeared in plasma 3 h after the juice ingestion, reached a peak between 5 and 7 h, then returned to baseline at 24 h. The peak plasma concentration of hesperetin was 0.46 AE 0.07 mmol=l and 1.28 AE 0.13 mmol=l after the 0.5 and 1 l intake, respectively. It was lower for naringenin: 0.20 AE 0.04 mmol=l after the 1 l dose. The circulating forms of hesperetin were glucuronides (87%) and sulphoglucuronides (13%). For both flavanones, the urinary excretion was nearly complete 24 h after the orange juice ingestion. The relative urinary excretion was similar for hesperetin and naringenin and did not depend on the dose: values ranged from 4.1 AE 1.2 to 7.9 AE 1.7% of the intake. Conclusions: In case of a moderate or high consumption of orange juice, flavanones may represent an important part of the pool of total polyphenols present in plasma.

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“…Hesperidin and naringin are the main flavanone glycosides naturally occurring in citrus fruits (Rouseff et al, 1987;Kanaze et al, 2003). They exert antioxidant (RiceEvans et al, 1996;Miyake et al, 1998;Franke et al, 2005), anti-inflammatory (Crespo et al, 1999), blood lipid and cholesterol-lowering (Montforte et al, 1995;Bok et al, 1999;Lee et al, 1999;Santos et al, 1999) and anticarcinogenic activities Yang et al, 1997;Berkarda et al, 1998). Epidemiological studies indicate an association between the intake of citrus fruits and juices and the risk of ischemic stroke (Joshipura et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects

et al. 2006

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Background and objective: Hesperetin and naringenin, the aglycones of the flavanone glycosides hesperidin and naringin, occur naturally in citrus fruits. They exert interesting pharmacological properties such as antioxidant, anti-inflammatory, blood lipid and cholesterol lowering and are considered to contribute to health benefits in humans. However, no information is available on the pharmacokinetics of the citrus flavanones hesperetin and naringenin after their oral administration to humans as pure aglycones. Therefore, the objective of the present investigation was the evaluation of the pharmacokinetic parameters of hesperetin and naringenin in plasma and urine, after their single oral administration in humans in the form of solid dispersion capsules, and also to improve the absorption rate of flavanones by using aglycones rather than the naturally occurring glycosides. Design: Six healthy volunteers received orally 135 mg of each compound, hesperetin and naringenin, under fasting conditions. Blood samples were collected at 14 different time points over a 12 h period. Urine was collected over 24 h, in five sequential timed intervals. Plasma and urine hesperetin and naringenin concentrations, after enzymatic hydrolysis of their conjugated forms, were measured using validated high-pressure liquid chromatography methods. Pharmacokinetic parameters for hesperetin and naringenin, such as C max , T max , AUC 0Àt , AUC 0ÀN , CL/F, V/F, t 1/2 , MRT, A e , A e ( 0-24 ), and R max were calculated from their plasma or urine concentrations. Results: Pharmacokinetic analysis showed that both hesperetin and naringenin were rapidly absorbed and their concentrations in plasma observed 20 min after dosing and reached a peak in 4.0 and 3.5 h, respectively. The mean peak plasma concentration (C max ) for hesperetin and naringenin were 825.787410.63 ng/ml (2731.871358.4 nmol/l) and 2009.517770.82 ng/ml (7386.672833.4 nmol/l), respectively and the mean AUC 0ÀN values were 4846.2071675.99 ng h/ml and 9424.527 2960.52 ng h/ml for hesperetin and naringenin, respectively. The elimination half-life for hesperetin was found to be 3.0570.91 h and for naringenin 2.3170.40 h, respectively. The mean values of the relative cumulative urinary excretion, as percentage of the administered dose, for hesperetin and naringenin, were found to be 3.2670.44 and 5.8170.81%, respectively. Conclusions: Oral administration of the flavanone aglycones, hesperetin and naringenin, lead to their rapid absorption as their conjugated forms. The cumulative urinary recovery data indicated low bioavailability for both flavanone aglycones, owing to extensive first-pass metabolism partly by cleavage of the C-ring by the enzymes of intestinal bacteria leading to degradation products such as phenolic acids.

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Chemopreventive effects of diosmin and hesperidin on N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine‐induced urinary‐bladder carcinogenesis in male ICR mice

Cited by 48 publications

References 4 publications

Suppressive effect of 1,4-phenylene diisothiocyanate onN-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice

Suppressive effect of 1,4-phenylene diisothiocyanate onN-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice

Bioavailability in humans of the flavanones hesperidin and narirutin after the ingestion of two doses of orange juice

Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects

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