Chemoprevention of mammary carcinogenesis by hydroxylated derivatives of <i>d</i>-limonene

Crowell, Pamela L.; Kennan, Wendy S.; Haag, Jill D.; Ahmad, Saleem; Vedejs, E.; Gould, Michael N.

doi:10.1093/carcin/13.7.1261

Cited by 122 publications

(63 citation statements)

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“…The former prevent carcinogenic chemicals from interacting with target molecules, whereas the latter prevent the development and/or expression of the transformed cells. With respect to the mammary gland, agents such as retinoic acid (Welsch 1987, selenium (Ip & Medina 1987, and D-limonene (Crowell et al 1992) act as both blocking and suppressing agents, depending on the time intervals of application. It is more difficult to classify endogenous natural factors such as estrogen and progesterone.…”

Section: Protective Effect Of Pregnancymentioning

confidence: 99%

Mammary developmental fate and breast cancer risk

Medina

2005

Endocr Relat Cancer

108

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The ovarian hormones, estrogen and progesterone, play a pivotal role in normal and neoplastic development of the mammary gland. These hormones have a paradoxical role as long duration of estrogen and progesterone are associated with increased breast cancer risk, while short duration of pregnancy level doses are associated with a reduced breast cancer risk. The protective effects of estrogen and progesterone, as well as pregnancy, have been extensively studied in animal models. Recent studies have demonstrated that these hormones induce alterations in gene expression in the mammary epithelial cells which persist for a long time after the hormones are withdrawn from the host. It is postulated that hormones induce a switch in mammary developmental fate which decreases the risk of breast cancer over the lifetime of the host. Some of the possible cellular pathways persistently altered by short term hormone exposure are a decrease in growth factors and an increase in apoptosis. The expression of these genes, in turn, may be affected by alterations in genes regulating chromatin remodeling. The relative contributions of host-mediated factors and mammary cell intrinsic factors remain to be determined. The current studies have moved this research area from the biological to the molecular realm and offer the potential for directing prevention efforts at specific molecular targets.

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Section: Protective Effect Of Pregnancymentioning

confidence: 99%

Mammary developmental fate and breast cancer risk

Medina

2005

Endocr Relat Cancer

108

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“…The monocyclic monoterpene (ϩ)-and (Ϫ)-limonene enantiomers have been shown to be present in orange peel and other plants and are used as fragrances in household products and components of artificial essential oils (Crowell and Gould, 1994). The (ϩ)-limonene isomeric form is more abundantly present in these plants than the racemic mixture and (Ϫ)-isomeric form (Haudenschild et al, 2000).…”

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confidence: 99%

“…The (ϩ)-limonene isomeric form is more abundantly present in these plants than the racemic mixture and (Ϫ)-isomeric form (Haudenschild et al, 2000). It has previously been shown that (ϩ)-limonene has chemopreventive activities in experimental animal models including rats and mice (Crowell and Gould, 1994;el-Bayoumy, 1994). Some of the hydroxylated metabolites of (ϩ)-limonene, such as sobrerol, carveol, and uroterpenol, have been reported to be more potent than the parent compound in preventing mammary tumors caused by 7,12-dimethyldibenz [a]anthracene (Crowell et al, 1992).…”

mentioning

confidence: 99%

“…It has previously been shown that (ϩ)-limonene has chemopreventive activities in experimental animal models including rats and mice (Crowell and Gould, 1994;el-Bayoumy, 1994). Some of the hydroxylated metabolites of (ϩ)-limonene, such as sobrerol, carveol, and uroterpenol, have been reported to be more potent than the parent compound in preventing mammary tumors caused by 7,12-dimethyldibenz [a]anthracene (Crowell et al, 1992). To better understand the basis of mechanisms of chemopreventive action of limonene, it is of interest to examine the metabolism of limonene in experimental animals and humans.…”

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confidence: 99%

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Metabolism of (+)- and (−)-Limonenes to Respective Carveols and Perillyl Alcohols by CYP2C9 and CYP2C19 in Human Liver Microsomes

Miyazawa¹,

Shindo²,

Shimada³

2002

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Limonene, a monocyclic monoterpene, is present in orange peel and other plants and has been shown to have chemopreventive activities. (؉)-and (؊)-Limonene enantiomers were incubated with human liver microsomes and the oxidative metabolites thus formed were analyzed using gas chromatography-mass spectrometry. Two kinds of metabolites, (؉)-and (؊)-trans-carveol (a product by 6-hydroxylation) and (؉)-and (؊)-perillyl alcohol (a product by 7-hydroxylation), were identified, and the latter metabolites were found to be formed more extensively, the former ones with liver microsomes prepared from different human samples. Sulfaphenazole, flavoxamine, and antibodies raised against purified liver cytochrome P450 (P450) 2C9 that inhibit both CYP2C9-and 2C19-dependent activities, significantly inhibited microsomal oxidations of (؉)-and (؊)-limonene enantiomers. The limonene oxidation activities correlated well with contents of CYP2C9 and activities of tolbutamide methyl hydroxylation in liver microsomes of 62 human samples, whereas these activities did not correlate with contents of CYP2C19 and activities of S-mephenytoin 4-hydroxylation. Of 11 recombinant human P450 enzymes (expressed in Trichoplusia ni cells) tested, CYP2C8, 2C9, 2C18, 2C19, and CYP3A4 catalyzed oxidations of (؉)-and (؊)-limonenes to respective carveols and perillyl alcohol. Interestingly, human CYP2B6 did not catalyze limonene oxidations, whereas rat CYP2B1 had high activities in catalyzing limonene oxidations. These results suggest that both (؉)-and (؊)-limonene enantiomers are oxidized at 6-and 7-positions by CYP2C9 and CYP2C19 in human liver microsomes. CYP2C9 may be more important than CYP2C19 in catalyzing limonene oxidations in human liver microsomes, since levels of the former protein are more abundant than CYP2C19 in these human samples. Species-related differences exist in the oxidations of limonenes in CYP2B subfamily in rats and humans.

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“…Investigations of the in vivo disposition of d-limonene and its metabolites are limited. In rodents, radiolabeled d-limonene and/or its derived metabolites preferentially distribute to anatomical sites rich in fatty tissue such as adipose and mammary tissue rather than remaining in plasma [7]. Accurate assessment of the tissue distribution of d-limonene is a critical step to evaluate the potential of d-limonene as a chemopreventive agent in humans.…”

Section: Introductionmentioning

confidence: 99%

Determination of d-limonene in adipose tissue by gas chromatography–mass spectrometry

Miller¹,

Hakim²,

Thomson³

et al. 2008

Journal of Chromatography B

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We developed a novel method for analyzing d-limonene levels in adipose tissue. Fat samples were subjected to saponification followed by solvent extraction. d-Limonene in the sample extract was analyzed using gas chromatography-mass spectrometry (GC-MS) with selected ion monitoring. Linear calibration curves were established over the mass range of 79.0-2,529 ng d-limonene per 0.1 grams of adipose tissue. Satisfactory within day precision (RSD 6.7 to 9.6%) and accuracy (% difference of −2.7 to 3.8%) and between day precision (RSD 6.0 to 10.7%) and accuracy (% difference of 1.8 to 2.6%) were achieved. The assay was successfully applied to human fat biopsy samples from a d-limonene feeding trial.

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Chemoprevention of mammary carcinogenesis by hydroxylated derivatives of d-limonene

Cited by 122 publications

References 0 publications

Mammary developmental fate and breast cancer risk

Mammary developmental fate and breast cancer risk

Metabolism of (+)- and (−)-Limonenes to Respective Carveols and Perillyl Alcohols by CYP2C9 and CYP2C19 in Human Liver Microsomes

Determination of d-limonene in adipose tissue by gas chromatography–mass spectrometry

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