Studies on the Metabolism ofd-Limonene (p-Mentha-1,8-diene): II. The Metabolic Fate ofd-Limonene in Rabbits

Kodama, Ryuhei; Noda, Kanji; Ide, Hiroyuki

doi:10.3109/00498257409049348

Cited by 52 publications

(21 citation statements)

References 14 publications

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“…Following oral administration of R-limonene to male rabbits, Kodama et al (1974) [1161] identified several Phase I and Phase II metabolites in the urine, including p-mentha-1,8-dien-10-ol (M1), p-menth-1-ene-8,9-diol (uroterpenol, M2), perillic acid (M3), perillic acid 8,9-diol (M4), p-mentha-1,8-dien-10-yl -D-glucuronide (M5) and 8-hydroxy-p-menth-1-en-9-yl -D-glucuronide (M6). Later studies in other animal species identified five additional metabolites of dlimonene, namely, 2-hydroxy-p-menth-8-en-7-oic acid (M7), perillylglycine (M8), perillyl -D-glucuronide (M9), p-mentha-1,8-dien-6-ol (carveol, M10) and p-menth-1-ene- 6,8,9-triol (M11) [1158,1159].…”

Section: Limonenementioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

149

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Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

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Section: Limonenementioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

149

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“…In rat, terpenes accumulate in peripheral fat, kidneys, and brain (Savolainen and Pfaffli, 1978;Sperling et al, 1967). The renal elimination of 14 C-labeled d-limonene in rat and rabbit after oral administration was about 60-70% within 48 and 72 h, respectively (Igimi et al, 1974;Kodama et al, 1974). Terpenes may irritate the skin and mucous membranes (Grimm and Cries, 1983;Sandmeyer, 1983), and prolonged exposure may result in allergic contact dermatitis (Brun, 1975;Dooms-Goossens et al, 1977) or chronic lung function impairment (Hedenstierna et al, 1983).…”

Section: Introductionmentioning

confidence: 97%

d‐Limonene exposure to humans by inhalation: Uptake, distribution, elimination, and effects on the pulmonary function

Falk‐Filipsson

Löf²,

Hagberg³

et al. 1993

Journal of Toxicology and Environmental Health

102

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The toxicokinetics of d-limonene were studied in human volunteers exposed by inhalation (2 h, work load 50 W) in an exposure chamber on three different occasions. The exposure concentrations were approximately 10, 225, and 450 mg/m3 d-limonene. The relative pulmonary uptake was high, approximately 70% of the amount supplied. The blood clearance of d-limonene observed in this study, 1.1 l kg-1 h-1, indicates that d-limonene is metabolized readily. About 1% of the total uptake was eliminated unchanged in the expired air after the end of exposure, while approximately 0.003% was eliminated in the urine. A long half-time in blood was observed in the slow elimination phase, which indicates accumulation in adipose tissues. A decrease in vital capacity was observed after exposure to d-limonene at a high exposure level. The subjects did not experience any irritative symptoms or symptoms related to the central nervous system (CNS).

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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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Studies on the Metabolism ofd-Limonene (p-Mentha-1,8-diene): II. The Metabolic Fate ofd-Limonene in Rabbits

Cited by 52 publications

References 14 publications

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

d‐Limonene exposure to humans by inhalation: Uptake, distribution, elimination, and effects on the pulmonary function

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

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