Identification of metabolites of the antitumor agentd-limonene capable of inhibiting protein isoprenylation and cell growth

Abstract

Limonene has been shown to be an effective, nontoxic chemopreventive and chemotherapeutic agent in chemically induced rat mammary-cancer models. The present study characterized circulating metabolites of limonene in female rats and determined their effects on cell growth. Metabolism of limonene was analyzed in plasma extracts by gas chromatography. Rapid conversion of limonene to two major metabolites was detected. These metabolites comprised more than 80% of the circulating limonene-derived material at 1 h after administration and thereafter, whereas limonene itself accounted for only 15%. The metabolites were characterized by mass spectroscopy and infrared spectroscopy. The probable structures were synthesized, and identities were confirmed by comparison of retention times and mass spectra. The two major circulating metabolites of limonene were found to be perillic acid and dihydroperillic acid. We have previously reported that limonene, perillic acid, and dihydroperillic acid inhibit the posttranslational isoprenylation of p21ras and other 21- to 26-kDa cell-growth-associated proteins in NIH3T3 cells and in mammary epithelial cells. In the present study, perillic acid was found to inhibit cell growth in a dose-dependent manner. Thus, perillic acid and dihydroperillic acid, the two major circulating metabolites of limonene in the rat, are more potent inhibitors of protein isoprenylation than is limonene, and perillic acid is also a more potent inhibitor of cell growth. These data raise the possibility that the antitumor effects of limonene in vivo may be mediated via perillic acid and, perhaps, other metabolites.

Effect of the lemon essential oils on the safety and sensory quality of salted sardines ( Sardina pilchardus Walbaum 1792)

“…D-limonene is listed in the code of federal regulation as GRAS for use as a flavouring agent and in food preservation (Sun, 2007). Furthermore, several biochemical activities such as antimicrobial (Chikhoune, Hazzit, Kerbouche, Baaliouamer, & Aissat, 2013;Settanni et al, 2012;van Vuuren & Viljoen, 2007), antioxidant (Roberto, Micucci, Sebastian, Graciela, & Anesini, 2010), chemo-preventive (Crowell, Lin, Vedejs, & Gould, 1992;Wattenberg & Coccia, 1991), anticarcinogen (Crowell & Gould, 1994), as well as antidiabetic proprieties (Murali, Karthikeyan, & Saravanan, 2012) have been reported for D-limonene. The p-cymene, a biological precursor of carvacrol, is a hydrophobic chemical that might cause swelling of the cytoplasmic membrane of microorganisms (Ultee, Bennink, & Moezelaar, 2002).…”

Limonene Suppresses Lipopolysaccharide-Induced Production of Nitric Oxide, Prostaglandin E2, and Pro-inflammatory Cytokines in RAW 264.7 Macrophages

“…It is considered to be an ingredient with relatively low toxicity. Upon oral administration, D-limonene is rapidly and almost completely absorbed from the gastrointestinal tract of both humans and animals 3,4 . Other studies have shown that D-limonene does not pose a mutagenic, carcinogenic, or nephrotoxic risk to humans.…”

Heart and kidney oxidative stress status in septic rats treated with caraway extracts

“…First, the effectiveness of the essential oils in remedy of sepsis is probably due to pharmacokinetic properties and the disposition of the caraway monoterpenes in the body. Considering the physicochemical properties of the terpenes, such as lipophilicity and molecular mass and size, penetration into and permeation through the skin as well as subsequent systemic effects can be expected (Crowell et al, 1992;Phillips et al, 1995;Stott et al, 1998;Hongratanaworakit & Buchbauer, 2006). The presence of aromatic compound glucosides, alkyl glycosides, glucides, nucleoside, and flavonoids in hydroalcoholic fraction of caraway seeds (Matsumura et al, 2002) offer relatively poor bioavailability to this fraction.…”