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. 2002 May 28;99(11):7610-5.
doi: 10.1073/pnas.112203099.

Sulforaphane Inhibits Extracellular, Intracellular, and Antibiotic-Resistant Strains of Helicobacter Pylori and Prevents Benzo[a]pyrene-Induced Stomach Tumors

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Free PMC article

Sulforaphane Inhibits Extracellular, Intracellular, and Antibiotic-Resistant Strains of Helicobacter Pylori and Prevents Benzo[a]pyrene-Induced Stomach Tumors

Jed W Fahey et al. Proc Natl Acad Sci U S A. .
Free PMC article

Abstract

Gastric infection with Helicobacter pylori is a cosmopolitan problem, and is especially common in developing regions where there is also a high prevalence of gastric cancer. These infections are known to cause gastritis and peptic ulcers, and dramatically enhance the risk of gastric cancer. Eradication of this organism is an important medical goal that is complicated by the development of resistance to conventional antimicrobial agents and by the persistence of a low level reservoir of H. pylori within gastric epithelial cells. Moreover, economic and practical problems preclude widespread and intensive use of antibiotics in most developing regions. We have found that sulforaphane [(-)-1-isothiocyanato-(4R)-(methylsulfinyl)butane], an isothiocyanate abundant as its glucosinolate precursor in certain varieties of broccoli and broccoli sprouts, is a potent bacteriostatic agent against 3 reference strains and 45 clinical isolates of H. pylori [minimal inhibitory concentration (MIC) for 90% of the strains is <or=4 microg/ml], irrespective of their resistance to conventional antibiotics. Further, brief exposure to sulforaphane was bactericidal, and eliminated intracellular H. pylori from a human epithelial cell line (HEp-2). In complementary experiments, sulforaphane blocked benzo[a]pyrene-evoked forestomach tumors in ICR mice. This protection resulted from induction of phase 2 detoxication and antioxidant enzymes, and was abrogated in mice lacking the nrf2 gene, which regulates phase 2 enzymes. Thus, the dual actions of sulforaphane in inhibiting Helicobacter infections and blocking gastric tumor formation offer hope that these mechanisms might function synergistically to provide diet-based protection against gastric cancer in humans.

Figures

Figure 1
Figure 1
Bacteriostatic potency (minimal inhibitory concentration, MIC) of sulforaphane against 45 clinical isolates and 3 reference strains of H. pylori. Twenty-three bacterial strains were susceptible to clarithromycin (ClaS) and metronidazole (MetS), and the rest of the strains were resistant to clarithromycin (ClaR), metronidazole (MetR), or both antibiotics (ClaR MetR). Median MIC values for each of the four groups of strains were 2, 4, 4, and 2 μg/ml, respectively, and were not significantly different from each other. Each data point represents an individual strain, and means are indicated by horizontal bars.
Figure 2
Figure 2
Bactericidal potency of sulforaphane (SF) on two strains of H. pylori (A, LBN201, clinical isolate; B, 26695, reference strain) after exposure to 1× and 5× MIC of SF at pH 5.8. (Data points are the means of duplicate determinations; the asterisk indicates a point below the limits of detection.)
Figure 3
Figure 3
Eradication of intracellular bacterial infection in cultured HEp-2 cells after treatment with sulforaphane (SF) at 0.5×, 1×, and 5× the MIC for a clinical isolate (A, LBN201; 1, 2, and 10 μg/ml) and a reference strain (B, 26695; 2, 4, and 20 μg/ml) of H. pylori. HEp-2 cells were infected with H. pylori, extracellular bacteria were removed, and the mammalian cells were lysed at each sampling time to measure intracellular sulforaphane concentration and count cfu of H. pylori. Note the sharp demarcation between lack of activity (0.5× MIC) and bactericidal potency (1× MIC). Data points are the means of duplicate determinations; the asterisks indicate points below the limits of detection. Intracellular sulforaphane was calculated to be from 2- to 5-fold greater than initial external concentration, and gradually decreased over time.
Figure 4
Figure 4
Effect of sulforaphane on benzo[a]pyrene-induced neoplasia of the forestomach in female wild-type and nrf2-deficient mice. Female mice (9–12 wk old) were fed sulforaphane at an estimated intake of 7.5 μmol per animal per day, for a period extending from 7 days before, to 2 days after the last dose of carcinogen. Dosing with benzo[a]pyrene (120 mg/kg in 0.2 ml corn oil by gavage), was at four consecutive weekly intervals, and animals were killed 20 wk after the first benzo[a]pyrene treatment. Gastric tumors are reported as follows: (number of gastric tumors in the entire group)/(number of mice at risk at termination of experiment). Two animals in the nrf2-deficient control group had tumors too numerous to count. Open bar, vehicle-treated; filled bar, sulforaphane-treated. Error bars are ± SEM.

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