Disease relevance of C00521

• Carcinomas regress when limonene is added to the diet either when the tumor is small and still capable of spontaneously regressing or when it is large and progressed beyond the stage when it is susceptible to spontaneous regression [1].
• Monoterpenoids such as limonene represent a novel class of anticancer drugs with the potential to cause tumor regressions with limited toxicity [1].
• LEH is part of a novel limonene degradation pathway found in Rhodococcus erythropolis DCL14, where it catalyzes the hydrolysis of limonene-1,2-epoxide to give limonene-1,2-diol [2].
• MTBE dissolved cholesterol gall stones 100 times faster than mono-octanoin and 10 times faster than limonene or the limonene/mono-octanoin mixture (p less than 0.001) [3].
• Our findings suggest that limonene attenuates the gastric carcinogenesis enhanced by sodium chloride via increased apoptosis and decreased ODC activity in gastric cancers [4].

Psychiatry related information on C00521

• As expected, limonene administration increased the latency period and lowered the frequency of mammary carcinoma development as compared to controls [5].
• Responses to food frequency and dietary behavior questionnaires indicated a pattern of diet selection and food preferences that were consistent with a dietary origin for the limonene in these patients [6].

High impact information on C00521

• Nine cDNA isolates expressed sesquiterpene synthase activity, and GC-MS analysis of the products identified germacrene C with smaller amounts of germacrene A, B, and D. None of the expressed proteins was active with geranylgeranyl diphosphate; however, one truncated protein converted geranyl diphosphate to the monoterpene limonene [7].
• Search of the GenBank data base with the deduced translation product revealed 42% identity and 65% similarity with 5-epi-aristolochene synthase from tobacco and 31% identity and 53% similarity with limonene synthase from spearmint [8].
• On the basis of these observations, it was hypothesized that a possible mechanism by which limonene exerts its effects on the chemoprevention and regression of mammary tumors involves the inhibition of protein isoprenylation of the small G protein p21 [5].
• These studies are consistent with the above studies in that limonene is effective in preventing mammary carcinomas with activated ras [5].
• In addition, dietary limonene has been shown to be capable of preventing the development and causing the regression of chemically induced mammary carcinomas, many of which contain activated ras oncogenes [5].

Chemical compound and disease context of C00521

• We performed a pilot study on healthy human volunteers to identify plasma metabolites of limonene and to assess the toxicity of supradietary quantities of d-limonene [9].
• The levels of ethane, propane, n-pentane, methanol, ethanol, 2-propanol, acetone, isoprene, benzene, toluene, dimethyl sulphide (DMS) and limonene were measured in repeated breath samples from 20 cystic fibrosis patients and 20 healthy controls (aged 8-29 yrs) [10].
• Similar toxicity of monoterpenes was observed in TA100, E. coli SY252 and D7, with the exception of limonene (less toxic to D7) [11].
• The antiproliferative effect was evaluated in human prostate cancer LNCaP cells. l-Carvone, l-carveol, and l-limonene were weak cell growth inhibitors and introduction of 4-(2-methoxyphenyl)piperazine to carvone, carveol or limonene significantly increased their antiproliferative effect [12].
• Bioconversion of limonene to increased concentrations of perillic acid by Pseudomonas putida GS1 in a fed-batch reactor [13].

Biological context of C00521

• However, it should be noted that limonene can selectively inhibit the isoprenylation of small G proteins [1].
• Limonene modified neither the rate of gene transfer nor the stability of gene expression [5].
• Several nucleotide differences in the 5'-untranslated region of all three full-length clones suggest the presence of several limonene synthase genes and/or alleles in the allotetraploid spearmint genome [14].
• The R. erythropolis CDH gene (limC) was identified in an operon encoding the enzymes involved in limonene degradation [15].
• Given the recent discovery of the post-translational modification of p21ras and other cell growth-associated proteins by intermediates in the mevalonic acid pathway, and the common biochemical origins of limonene and these isoprene products, we investigated the effect of limonene on protein isoprenylation [16].

Anatomical context of C00521

• NIH3T3 and human mammary epithelial cells were incubated with lovastatin and [2-14C]mevalonolactone in the absence and presence of limonene [16].
• Limonene is metabolized extensively in vivo but not in cultured cells [16].
• Limonene inhibited isoprenylation of a class of cellular proteins of 21-26 kDa, including p21ras and possibly other small GTP-binding proteins, in a dose-dependent manner in both cell lines [16].
• These findings indicate that limonene inhibits hepatocarcinogenesis and suggest that this effect may be clearly related to its effect in inhibiting cell proliferation and in enhancing apoptosis, but not through ras oncoprotein plasma membrane association [17].
• POH, but not limonene selectively induced G0/G1 arrest followed by apoptosis in Bcr/Abl-transformed, but not nontransformed FDC.P1 and 32D myeloid cell lines [18].

Associations of C00521 with other chemical compounds

• Monoterpenes, including limonene and its in vivo rat plasma metabolites, have been shown to be inhibitors of protein isoprenylation of small G proteins, including p21 ras [5].
• The two major rat serum metabolites of limonene, perillic acid and dihydroperillic acid, were more potent than limonene in the inhibition of isoprenylation [16].
• These results demonstrate that limonene selectively inhibits isoprenylation of 21-26-kDa proteins at a point in the mevalonic acid pathway distal to 3-hydroxy-3-methylglutaryl coenzyme A reductase, and they provide a plausible explanation for its chemotherapeutic activity [16].
• In this study we compared the in vitro dissolving capacity of methyl tert-butyl ether (MTBE), mono-octanoin, limonene, and limonene/mono-octanoin (70%/30%) [3].
• The 5% limonene diet increased total CYP to the same extent as phenobarbital (PB) treatment when compared to control, while 1% sobrerol (isoeffective in chemoprevention to 5% limonene) did not [19].

Gene context of C00521

• 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 [20].
• Interestingly, human CYP2B6 did not catalyze limonene oxidations, whereas rat CYP2B1 had high activities in catalyzing limonene oxidations [20].
• Western blot analysis has shown inhibition of YY1 protein in NDEA induced liver tumor samples in comparison to normal and both NDEA and limonene treated samples [21].
• Limonene has chemotherapeutic activity against chemically induced rat mammary carcinomas, many of which contain activated ras genes [16].
• Hydroxylation of specifically deuterated limonene enantiomers by cytochrome p450 limonene-6-hydroxylase reveals the mechanism of multiple product formation [22].

Analytical, diagnostic and therapeutic context of C00521

• Limonene chemoprevention of mammary carcinoma induction following direct in situ transfer of v-Ha-ras [5].
• Furthermore, polyclonal antibodies raised against the angiosperm limonene synthase did not detectably cross-react with any proteins in extracts from either lodgepole pine or grand fir by immunoblotting analysis [23].
• At week 16, quantitative histologic analysis showed that oral administration of 1% or 2% limonene resulted in significant reductions in the number and mean area of GST-P-positive hepatic foci and the number of cellular alteration foci, neoplastic nodules and hepatocellular carcinomas [17].
• In solution both enantiomers of limonene induce significant changes in the visible and circular dichroism (CD) spectra of [Co2(1)], while a different behavior is observed in the case of the enantiomeric pair of trans-1,2-diaminocyclohexane [24].
• Reversibility studies showed that the post-recovery passive flux of LHRH through 5% limonene in EtOH/iontophoresis treated epidermis was significantly (p < 0.05) decreased but did not significantly recover to the baseline flux (i.e., flux through control epidermis) [25].

References