A comparative study on the metabolism of<i>d</i>-limonene and 4-vinylcyclohex-1-ene by hepatic microsomes

Watabe, Tadashi; Hiratsuka, Akira; Ozawa, Naok̆i; Isobe, Masakazu

doi:10.3109/00498258109045312

Cited by 64 publications

(28 citation statements)

References 20 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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“…All three compounds were tested in the presence and in the absence of PCB-induced rat liver activation system at concentrations up to 0.1 pmol/plate; cytotoxic effects were noted at lpmol/plate Watabe et al, , 1981. Florin and coworkers (1980) reported similar negative results for limonene in S. typhimurium TA98, TA100, TA1535 and TA1537 in the presence or absence of iiethylcholanthrene-induced rat liver homogenate at concentrations up to 0.3 pmol/plate.…”

Section: Mutagenicitymentioning

confidence: 58%

“…The presence of the epoxide hydrolase inhibitor, 3,3,3-trichloropropene 1,2-oxide, completely inhibited microsomal hydrolysis of the 8,9-epoxide formed from d-lir;ionene and resulted in its accumulation in the reaction medium without yielding any detectable amount of the 8,9-glycol (Watabe et al, 1981). Regan et al (1980) also reported that limonene-1,2-epoxide was not a major intermediate of limonene metabolism in the rat.…”

Section: Mutagenicitymentioning

confidence: 99%

Development of Candidate Chemical Simulant List: The Evaluation of Candidate Chemical Simulants Which May Be Used in Chemically Hazardous Operations

CAMBRIDGE¹

1982

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“…No further details about dose, recovery or nature of the conjugates (whether phenolic or alcoholic; sulphate or glucuronide) were available. Based on observations with vanillyl acetone (see above) ring hydroxylation may also have occured with 5-paradol, but such metabolites were not reported and it is not clear whether such metabolites have been looked for (Watabe et al, 1981; only abstract available).…”

Section: -Methoxyphenolmentioning

confidence: 99%

Scientific Opinion on Flavouring Group Evaluation 22, Revision 1 (FGE.22Rev1): Ring‐substituted phenolic substances from chemical groups 21 and 25

Flavourings¹

2011

EFS2

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The Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids of the European Food Safety Authority was requested to evaluate 28 flavouring substances in the Flavouring Group Evaluation 22, Revision 1, using the Procedure in Commission Regulation (EC) No 1565/2000. The substance 3,4-methylenedioxyphenol [FL-no: 04.080] was reported to have a genotoxic potential in vitro, while in vivo studies were not available. Therefore, the Panel concluded that the Procedure could not be applied to this substance until adequate genotoxicity data become available. The remaining 27 substances were evaluated through a stepwise approach (the Procedure) that integrates information on structure-activity relationships, intake from current uses, toxicological threshold of concern, and available data on metabolism and toxicity. The Panel concluded that these 27 candidate substances do not give rise to safety concerns at their levels of dietary intake, estimated on the basis of the MSDI approach. Adequate specifications for the materials of commerce are available for all 27 flavouring substances evaluated through the Procedure.

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A comparative study on the metabolism ofd-limonene and 4-vinylcyclohex-1-ene by hepatic microsomes

Cited by 64 publications

References 20 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

Development of Candidate Chemical Simulant List: The Evaluation of Candidate Chemical Simulants Which May Be Used in Chemically Hazardous Operations

Scientific Opinion on Flavouring Group Evaluation 22, Revision 1 (FGE.22Rev1): Ring‐substituted phenolic substances from chemical groups 21 and 25

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