Disease relevance of C06099

• In these experiments D-limonene and D-carvone were tested and reduced forestomach tumor formation by slightly over 60% and pulmonary adenoma formation by about 35% [1].
• We have shown that d-limonene induces the regression of advanced rat mammary adenocarcinomas [2].
• No toxicity was evident in these rats even at the highest d-limonene dose [3].
• d-Limonene was found to be effective in reducing the average number of rat mammary carcinomas that developed in 7,12-dimethylbenz[a]anthracene-treated rats when the terpene was fed during the initiation or during the promotion/progression stage of carcinogenesis [4].
• However, in rats given both sodium chloride and d-limonene, the incidence of gastric cancers, the labeling index and ODC activity were significantly lower and the apoptotic index was significantly higher than in rats given sodium chloride alone [5].

High impact information on C06099

• Quercetin, d-limonene, and all-trans retinoic acid each had no effect on spontaneous tumor development in p53-/- mice [6].
• The presence of alpha 2u-globulin is necessary for d-limonene promotion of male rat kidney tumors [7].
• In a 2-year carcinogenesis bioassay, d-limonene (dL) induced kidney tumors in male F344 rats, but not in female F344 rats or either sex of mice, d-Limonene-1,2-oxide, a metabolite of dL, has been shown to bind reversibly the male rat-specific urinary protein, alpha2u-globulin (alpha 2u-G), lysosomal degradation than alpha 2u-G alone [7].
• Selective inhibition of isoprenylation of 21-26-kDa proteins by the anticarcinogen d-limonene and its metabolites [8].
• With administration of sufficient doses of d-limonene to male rats, this protein has been found to accumulate excessively in the P2 segment cells of renal proximal tubules, resulting in hyaline droplet formation as a manifestation of protein overload [9].

Chemical compound and disease context of C06099

• The monocyclic monoterpenoid d-limonene and its source, orange oil, were found to prevent rat mammary carcinomas induced by the direct-acting carcinogen nitrosomethylurea [10].
• Modulation of the mevalonate pathway and cell growth by pravastatin and d-limonene in a human hepatoma cell line (Hep G2) [11].
• Biotransformation of D-limonene to (+) trans-carveol by toluene-grown Rhodococcus opacus PWD4 cells [12].
• Of all the monoterpenes examined, D-limonene exhibited the strongest oral toxicity and induced the severest aversive behavior with vomiting and/or excretion in the fly [13].
• Alterations considered to be sequelae of the hyaline droplet response, including granular casts in the outer zone of the medulla and multiple cortical changes collectively classified as chronic nephrosis, were present in the kidneys of both decalin- and d-limonene-treated rats killed on day 27 [14].

Biological context of C06099

• This proposed mechanism has been supported by additional information, including negative genotoxicity tests for d-limonene and its oxide metabolites, experimentally verified tumor promotion, and enhanced cell proliferation primarily in P2 segment tubule cells in male F344 rats, but no such effects in the alpha 2U-g-deficient NBR rat [9].
• The results of isotopically sensitive branching experiments of competitive and noncompetitive design were consistent with a nondissociative kinetic mechanism, indicating that (4R)-limonene has sufficient freedom of motion within the active site of CYP71D18 to allow formation of either the trans-3- or cis-6-hydroxylated product [15].
• Pharmacokinetics of perillic acid in humans after a single dose administration of a citrus preparation rich in d-limonene content [16].
• Comparative analysis of percutaneous absorption enhancement by d-limonene and oleic acid based on a skin diffusion model [17].
• Further studies with large sample sizes are needed to more completely evaluate the interrelationships between peel intake, bioavailability of d-limonene, and other lifestyle factors [18].

Anatomical context of C06099

• Inhibition by d-limonene of experimental hepatocarcinogenesis in Sprague-Dawley rats does not involve p21(ras) plasma membrane association [19].
• The effects of d-limonene intake on ornithine decarboxylase (ODC) activity and on the silver stained nucleolar organizer region protein (AgNOR) count in the colonic mucosa were also estimated [20].
• Metabolism of d-limonene by hepatic microsomes to non-mutagenic epoxides toward Salmonella typhimurium [21].
• With d-limonene as a model hyaline droplet inducing agent, both rat and mouse liver microsomes oxidized the terpene to its 1,2-epoxide (the metabolite that binds reversibly to alpha 2u-globulin in vivo), demonstrating that metabolic differences do not determine the mouse resistance to this lesion [22].
• Perillic acid, a major metabolite of d-limonene, substantially suppressed interleukin-2 (IL-2) and IL-10 production in mitogen-activated T lymphocytes [23].

Associations of C06099 with other chemical compounds

• Attenuation by d-limonene of sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats [5].
• We here report that treatment of phytohemagglutinin-stimulated peripheral blood mononuclear cells with monoterpenes including d-limonene, perillic acid and perillyl alcohol (0.5-5 mM) which selectively inhibit the isoprenylation of 21-26-kDa proteins resulted in a dose-dependent inhibition of DNA synthesis [24].
• The effects of d-limonene on hepatocarcinogenesis induced by N-nitrosomorpholine (NNM) and on membrane-associated p21(ras) and labeling and apoptotic indices of the liver were investigated in male Sprague-Dawley rats [19].
• Inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone carcinogenesis in mice by D-limonene and citrus fruit oils [25].
• Ciprofibrate represses alpha 2u-globulin expression in liver and inhibits d-limonene nephrotoxicity [26].

Gene context of C06099

• However, along with our earlier information about c-myc with the present study, clearly indicated the involvement of YY1 in NDEA induced hepatocarcinogenesis and d-limonene mediated chemoprevention which might be regulated by c-myc oncoprotein [27].
• d-limonene chemoprevention of hepatocarcinogenesis in AKR mice: inhibition of c-jun and c-myc [28].
• We have also shown that the chemopreventive monoterpene, d-limonene, can prevent ras-induced mammary tumors in this model.(ABSTRACT TRUNCATED AT 250 WORDS)[29]
• The monoterpene d-limonene inhibits the post-translational isoprenylation of p21ras and other small G proteins, a mechanism that may contribute to its efficacy in the chemoprevention and therapy of chemically induced rodent cancers [30].
• Design of a gas chromatograph with parallel radioactivity and mass spectrometric detection. Application to the identification of the major metabolite of d-limonene associated with alpha 2u-globulin [31].

Analytical, diagnostic and therapeutic context of C06099

• Chemoprevention of mammary carcinogenesis by hydroxylated derivatives of d-limonene [32].
• The two control groups had no tumors and the d-limonene group had one tumor of the prostate, which was considered spontaneous [33].
• Blood samples were collected for up to 24 h after the completion of lemonade consumption. d-Limonene levels in the juice and perillic acid levels in plasma were determined by reversed-phase high-performance liquid chromatography with UV detection [16].
• The results indicated that, 24 hr after oral administration of 3 mmol d-limonene/kg, the renal concentration of d-limonene equivalents was approximately 2.5 times higher in male rats than in female rats [34].
• Phase I and pharmacokinetic study of D-limonene in patients with advanced cancer. Cancer Research Campaign Phase I/II Clinical Trials Committee [35].

References