Studies on the Metabolism of<i>d</i>-Limonene (<i>p</i>-mentha-1, 8-diene). IV Isolation and Characterization of New Metabolites and Species Differences in Metabolism

Kodama, Ryuhei; Yano, Tadanori; Furukawa, Kazuhide; Noda, Kanji; Ide, Hiroyuki

doi:10.3109/00498257609151649

Cited by 107 publications

(55 citation statements)

References 17 publications

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“…Metabolism of limonene enantiomers has been studied extensively in experimental animal models in rats, mice, rabbits, guinea pigs, and dogs both in vivo and in vitro (Igimi et al, 1974;Kodama et al, 1974Kodama et al, , 1976Regan and Bjeldanes, 1976;Watabe et al, 1981). Cytochrome P450 (P450 1 ) enzymes in liver microsomes of these animal species have been shown to oxidize limonene to several oxidation products such as 1,2-and 8,9-epoxides, carveol (a product by 6-hydroxylation), perillyl alcohol (a product by 7-hydroxylation) (Watabe et al, 1980(Watabe et al, , 1981Jager et al, 1999).…”

mentioning

confidence: 99%

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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mentioning

confidence: 99%

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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“…Humans produce limonene-1,2-diol in addition to these two serum metabolites (Crowell et al 1994). On the other hand, glycine and glucuronide conjugates of perillic acid and uroterpenol (p-mentha-8,9-diol) have been detected in the urine of many limonene-fed mammals (Kodama et al 1976;Regan and Bjeldanes 1976). Yeruva et al (2007) reported that perillic acid elicited dose-dependent cytotoxicity, induced cell cycle arrest and apoptosis with increasing expression of bax, p21 and caspase-3 activity in non small cell lung cancer (NSCLC, A549, and H520) lines.…”

Section: Discussionmentioning

confidence: 99%

Genotoxic and oxidative damage potentials in human lymphocytes after exposure to terpinolene in vitro

et al. 2014

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Terpinolene (TPO) is a monocyclic monoterpene found in the essential oils of various fir and pine species. Recent reports indicated that several monoterpenes could exhibit antioxidant effects in both human and animal experimental models. However, so far, the nature and/or biological roles of TPO have not been elucidated in human models yet. The aim of this study was to investigate the genetic, oxidative and cytotoxic effects of TPO in cultured human blood cells (n = 5) for the first time. Human blood cells were treated with TPO (0-200 mg/L) for 24 and 48 h, and then cytotoxicity was detected by lactate dehydrogenase (LDH) release and [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay, while DNA damage was also analyzed by micronucleus assay, sister chromatid exchanges assay and 8-oxo-2-deoxyguanosine (8-OH-dG) level. In addition, biochemical parameters [total antioxidant capacity (TAC) and total oxidative stress (TOS)] were examined to determine oxidative effects. The results of LDH and MTT assays showed that TPO (at concentrations greater than 100 mg/L) decreased cell viability. In our in vitro test systems, it was observed that TPO had no genotoxicity on human lymphocytes. Again, TPO (at 10, 25, 50 and 75 mg/L) treatment caused statistically important (p \ 0.05) increases of TAC levels in human lymphocytes without changing TOS levels. In conclusion, TPO can be a new resource of therapeutics as recognized in this study with its non-genotoxic and antioxidant features.

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“…No unchanged D-limonene was detected in urine of the rabbit. Urinary metabolites are excreted within 24-72 hours and represents 82-96 % of the dose in rodents and rabbits, 77 % in dogs and 55-83 % in humans, (Kodama et al, , 1976Igimi et al, 1974;and as referenced in EFSA CEF Panel, 2011b). Excretion via faeces represents 2-9 % in rodents and rabbits and 9 % in dogs.…”

Section: Absorption Distribution Metabolism and Excretion (Adme) Anmentioning

confidence: 99%

Scientific Opinion on the safety and efficacy of aliphatic and aromatic hydrocarbons (chemical group 31) when used as flavourings for all animal species

2015

EFSA Journal

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Chemical group 31 consists of aliphatic and aromatic hydrocarbons, of which 17 are currently authorised for use as flavours in food. This opinion concerns nine compounds from this group. The Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) is unable to perform an assessment of 1,4(8), 12-bisabolatriene [01.016] due to the lack of data on its purity. The Panel concludes that D-limonene [01.045] is safe for all animal species, except for male rats, at the proposed maximum dose level (25 mg/kg feed). 1-Isopropyl-4-methylbenzene [01.002] is safe for all target species, except cats, at the proposed maximum dose level (25 mg/kg feed), with a margin of safety ranging from 1-fold (no margin of safety) to 3. [01.046], the calculated safe use level is 1.5 mg/kg complete feed for cattle, salmonids and non-food-producing animals and 1 mg/kg complete feed for pigs and poultry. The absence of a margin of safety would not allow the simultaneous administration in feed and water for drinking of these substances. Overall, the FEEDAP Panel is not in the position to conclude on the use of these additives in water for drinking. No safety concern would arise for the consumer from the use of these compounds up to the highest safe levels in feeds. All compounds should be considered irritant to skin, eyes and respiratory tract and as skin sensitisers. No risk for the safety for the environment is foreseen. Since all of the compounds under assessment are used in food as flavourings, and their function in feed is essentially the same as that in food, no further demonstration of efficacy is necessary. No safety concern would arise for the consumer from the use of these compounds up to the highest safe levels in feeds.All compounds should be considered irritant to skin, eyes and respiratory tract and as skin sensitisers.No risk for the safety for the environment is foreseen.

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Studies on the Metabolism ofd-Limonene (p-mentha-1, 8-diene). IV Isolation and Characterization of New Metabolites and Species Differences in Metabolism

Cited by 107 publications

References 17 publications

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

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

Genotoxic and oxidative damage potentials in human lymphocytes after exposure to terpinolene in vitro

Scientific Opinion on the safety and efficacy of aliphatic and aromatic hydrocarbons (chemical group 31) when used as flavourings for all animal species

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