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

Abstract

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.

Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products

“…Farnesylation is essential for embryonic development [279] and Farnesyl and geranylphosphate play a role in angiogenesis in human umbilical endothelial cells [280,281]. Limonene is metabolised by cytochrome p5450's CYP2C9 and CYP2C19 [282] both of which metabolise progesterone, while testosterone is a substrate for CYP2C19 [283].…”

Effect of soy oil, orange (<em>Citrus sinensis</em>) peel oil and their blends on total phospholipid, lipid peroxidation, and antioxidant defense system in brain tissues of normo rats

“…Dietary fatty acids (especially docosahexaenoic acid [22:6(n-3)] (DHA)) play a major role in the chemistry and function of both developing and mature brain contents of the mammalian brain (Innis, 2005). (+)-and (−)-trans-carveol, and (+)-and (−)-perillyl alcohol have been reported as the principle metabolites of limonene (Miyazawa et al, 2002). The enantiomers of perillyl alcohol are being viewed as novel therapeutic alternatives in some CNS neoplasms and other solid tumours, particularly for the treatment of gliomas (Fonseca et al, 2011).…”

Metabolism of (+)-Fenchone by CYP2A6 and CYP2B6 in Human Liver Microsomes

“…[13][14][15][16] The metabolite from monoterpene esthers have determined to be oxidized at the 2-position of the molecules (1,4-cineole and 1,8-cineole) by human CYP3A4 enzyme. 13,14) Limonene enatiomers are metabolized to their respective carveols and perillyl alcohols in human liver.…”