Breast cancer prevention: present and future

Salih, Ali; Fentiman, Ian S.

doi:10.1053/ctrv.2001.0235

Cited by 35 publications

(14 citation statements)

References 95 publications

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“…The dose of tamoxifen and raloxifene used in rats in the present study, 1 mg/kg/day, is lower than the therapeutic doses given to patients (i.e. 20 mg/day of tamoxifen and 60 or 120 mg/day of raloxifene) (33, 34). Thus, it is possible that tamoxifen and raloxifene could also increase striatal DAT specific binding in women receiving them.…”

Section: Discussionmentioning

confidence: 68%

Influence of Oestrogenic Compounds on Monoamine Transporters in Rat Striatum

Saux

Paolo

2005

J Neuroendocrinology

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Oestrogens have been reported to modulate rat membrane (DAT) and vesicular (VMAT(2)) dopamine transporters. A recent pilot study of postmenopausal women showed that chronic oestrogen replacement therapy increases striatal DAT. In the present study, we first investigated whether the oestrogen receptors alpha and beta mediate the effects of oestradiol on DAT and VMAT(2). Two days after ovariectomy, Sprague-Dawley rats were treated for 2 weeks with oestradiol or specific ligands for oestrogen receptor alpha, 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) or oestrogen receptor beta, 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN). Ovariectomy caused a decrease in [(125)I]-3beta-(4-iodophenyl)-tropane-2beta-carboxylic acid isopropyl ester ([(125)I] RTI-121) specific binding to DAT transporters in the middle striatum compared to values for intact rats, and this was reversed by oestradiol replacement therapy. DPN, but not PPT, mimicked the effect of oestradiol. [(125)I] RTI-121 specific binding in the anterior and posterior striatum was not affected by ovariectomy or any of the drug treatments. Second, we investigated whether oestradiol increased DAT specific binding after a longer period of hormonal withdrawal (a model of hormonal withdrawal at menopause) and whether the selective oestrogen receptor modulators (SERMs), tamoxifen and raloxifene, could reproduce the oestradiol-induced increase of [(125)I] RTI-121 specific binding in long-term ovariectomised rats. Four months after ovariectomy, Sprague-Dawley rats were treated for 2 weeks with oestradiol, tamoxifen or raloxifene, and then killed. Ovariectomy decreased [(3)H] RTI-121 specific binding to DAT transporters in the middle striatum compared to values for intact rats. Treatment with oestradiol, tamoxifen and raloxifene reversed this effect. [(125)I] RTI-121 specific binding in anterior and posterior striatum was not affected by ovariectomy or treatment with oestrogen receptor ligands. In both experiments, neither ovariectomy nor the oestrogenic treatments modulated striatal [(3)H] tetrahydrobenazine specific binding to VMAT(2). Overall, these results suggest that oestrogen receptor beta mediates the oestradiol-induced increase of striatal DAT and that oestradiol can increase DAT density even after long-term steroid withdrawal. The results also support the premise that the SERMs tamoxifen and raloxifene exert oestrogenic agonist effects in the brain.

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Section: Discussionmentioning

confidence: 68%

Influence of Oestrogenic Compounds on Monoamine Transporters in Rat Striatum

Saux

Paolo

2005

J Neuroendocrinology

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“…Chemoprevention refers to the application of natural or synthetic compounds to block, reverse, or prevent the development of invasive cancers [212,[418][419][420][421]. For example, tamoxifen and raloxifene (both oestrogen receptor modulators) reduce the risk of developing breast cancer in women at increased risk [422,423]. For example, tamoxifen and raloxifene (both oestrogen receptor modulators) reduce the risk of developing breast cancer in women at increased risk [422,423].…”

Section: Mechanism-based Inhibition Of Cyps and Herbal Chemopreventionmentioning

confidence: 99%

Metabolic Activation of Herbal and Dietary Constituents and Its Clinical and Toxicological Implications: An Update

Zhou¹,

Xue²,

Yu³

et al. 2007

CDM

118

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In recent years, there has been a globally increasing application of herbal medicines and dietary supplements to treat various chronic diseases and to promote health. However, there are increasing clinical reports on the organ toxicities associated with consumption of herbal medicines. This review updates the knowledge on metabolic activation of herbal components and its clinical and toxicological implications. Like many synthetic drugs undergoing metabolic activation to form reactive metabolites which are often associated with drug toxicity, it is recognized that some herbal components may also be converted to toxic, or even mutagenetic and carcinogenic metabolites by cytochrome P450s (CYPs) and less frequently by Phase II conjugating enzymes. This is exemplified by aristolochic acids (AAs) in Aristolochia spp, which undergo reduction of the nitro group by hepatic CYP1A1/2 or peroxidases in extrahepatic tissues to generate highly reactive cyclic nitrenium ions. The latter can react with macromolecules (DNA and protein), resulting in activation of H-ras oncogene and gene mutation in renal cells and finally carcinogenesis of the kidneys. Some naturally occurring flavonoids (e.g. quercetin) and alkenylbenzenes (e.g. safrole, methyleugenol and estragole) can undergo metabolic activation by sequential 1-hydroxylation and sulfation, resulting in reactive intermediates capable of forming DNA adducts and finally genotoxicity. Additional examples are pulegone present in essential oils from many mint species; and teucrin A, a diterpenoid found in germander (Teuchrium chamaedrys) used as an adjuvant to slimming dietary supplements but caused severe hepatotoxicity. Extensive pulegone metabolism generated p-cresol that was a glutathione depletory, whereas the furan ring of the diterpenoids in germander was oxidized by CYP3A4 to reactive epoxide which can inactivate hepatic CYP3A and epoxide hydrolase through covalent binding. The hepatotoxic and carcinogenic species of plant pyrrolizidine alkaloids (e.g. echimidine and jacobine), namely pyrrole-type metabolites, are generated by hepatic CYP2B6 and CYP3A4. Potential mechanisms underlying the hepatotoxicity of kava have been related to intracellular glutathione depletion and/or quinone formation. Some herbal constituents (e.g. capsaicin from chili peppers, glabridin from licorice root, oleuropein in olive oil, dially sulfone in garlic, and resveratrol found in red wine) behave as mechanism-based inhibitors of various CYPs. This may provide an explanation for some reported herb-drug interactions. In addition, the inhibition of CYPs by herbal constituents may decrease the formation of toxic metabolites and thus inhibit carcinogenesis, as CYPs play an important role in procarcinogen activation. Due to the wide use and easy availability of herbal medicines, further research should be conducted to ensure the safety and quality of herbal medicine.

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“…Clinical evidence has indicated the feasibility of this approach in reducing the risk of major human cancers. For example, tamoxifen and raloxifene (both oestrogen receptor modulators) reduce the risk of developing breast cancer in women at increased risk (Fisher et al, 1998;Salih and Fentiman, 2001). Results with aspirin and non-steroidal anti-inflammatory agents have proved consistently encouraging in epidemiological studies in lowering the incidence of colorectal cancer (Jolly et al, 2002).…”

Section: Mechanism-based Inhibition Of Cyps and Herbal Chemopreventionmentioning

confidence: 99%

Herbal bioactivation: The good, the bad and the ugly

et al. 2004

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It has been well established that the formation of reactive metabolites of drugs is associated with drug toxicity. Similarly, there are accumulating data suggesting the role of the formation of reactive metabolites/intermediates through bioactivation in herbal toxicity and carcinogenicity. It has been hypothesized that the resultant reactive metabolites following herbal bioactivation covalently bind to cellular proteins and DNA, leading to toxicity via multiple mechanisms such as direct cytotoxicity, oncogene activation, and hypersensitivity reactions. This is exemplified by aristolochic acids present in Aristolochia spp, undergoing reduction of the nitro group by hepatic cytochrome P450 (CYP1A1/2) or peroxidases in extrahepatic tissues to reactive cyclic nitrenium ion. The latter was capable of reacting with DNA and proteins, resulting in activation of H-ras oncogene, gene mutation and finally carcinogenesis. Other examples are pulegone present in essential oils from many mint species; and teucrin A, a diterpenoid found in germander (Teuchrium chamaedrys) used as an adjuvant to slimming diets. Extensive pulegone metabolism generated p-cresol that was a glutathione depletory, and the furan ring of the diterpenoids in germander was oxidized by CYP3A4 to reactive epoxide which reacts with proteins such as CYP3A and epoxide hydrolase. On the other hand, some herbal/dietary constituents were shown to form reactive intermediates capable of irreversibly inhibiting various CYPs. The resultant metabolites lead to CYP inactivation by chemical modification of the heme, the apoprotein, or both as a result of covalent binding of modified heme to the apoprotein. Some examples include bergamottin, a furanocoumarin of grapefruit juice; capsaicin from chili peppers; glabridin, an isoflavan from licorice root; isothiocyanates found in all cruciferous vegetables; oleuropein rich in olive oil; dially sulfone found in garlic; and resveratrol, a constituent of red wine. CYPs have been known to metabolize more than 95% therapeutic drugs and activate a number of procarcinogens as well. Therefore, mechanism-based inhibition of CYPs may provide an explanation for some reported herb-drug interactions and chemopreventive activity of herbs. Due to the wide use and easy availability of herbal medicines, there is increasing concern about herbal toxicity. The safety and quality of herbal medicine should be ensured through greater research, pharmacovigilance, greater regulatory control and better communication between patients and health professionals.

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Breast cancer prevention: present and future

Cited by 35 publications

References 95 publications

Influence of Oestrogenic Compounds on Monoamine Transporters in Rat Striatum

Influence of Oestrogenic Compounds on Monoamine Transporters in Rat Striatum

Metabolic Activation of Herbal and Dietary Constituents and Its Clinical and Toxicological Implications: An Update

Herbal bioactivation: The good, the bad and the ugly

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