In vitro inhibition of CYP2B1 monooxygenase by myrcene and other monoterpenoid compounds

Department of Biological Sciences, The National School for Public Health, Oswaldo Cruz foundation, Rio de Janeiro, Brazil.
Toxicology Letters (Impact Factor: 3.26). 06/1997; 92(1):39-46. DOI: 10.1016/S0378-4274(97)00034-9
Source: PubMed


beta-myrcene (MYR) is an acyclic monoterpene found in the essential oils of several useful plants such as lemongrass (Cymbopogon citratus), hop, bay, verbena and others. Recently it has been reported that MYR as well as lemongrass oil blocked the metabolic activation of some promutagens (e.g., cyclophosphamide and aflatoxin B1) in in vitro genotoxicity assays. The present study was performed to evaluate the inhibitory effects of MYR and some other monoterpenoid compounds on microsomal enzymes involved in the activation of genotoxic substances. The effects of MYR and other monoterpenes on the activity of pentoxyresorufin-O-depenthylase (PROD), a selective marker for CYP2B1, was determined in a pool of liver microsomes prepared from phenobarbital-treated rats. The effect of MYR on the activity of ethoxyresorufin-O-deethylase (EROD), a marker for CYP4501A1, was investigated in liver microsomes of untreated rats. Results revealed that MYR had almost no effect on EROD (IC50 > 50 microM), but produced a concentration-dependent inhibition of PROD activity (IC50 =0.14 microM). The analysis of alterations produced by MYR on PROD kinetic parameters (Lineweaver-Burk plot) suggested that inhibition is competitive (Ki = 0.14 microM). The inhibitory effects of seven other monoterpenes on PROD activity (pentoxyresorufin 5 microM) were also studied and the IC50 were as follows: (-)-alpha-pinene, 0.087 microM; (+)-alpha-pinene, 0.089 microM; d-limonene, 0.19 microM; alpha-terpinene, 0.76 microM; citral, 1.19 microM; citronellal, 1.56 microM, and (+/-) camphor, 7.89 microM. The potent inhibitory effects on CYP4502B1 suggest that MYR, and other monoterpenes, interfere with the metabolism of xenobiotics which are substrates for this isoenzyme.

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    • "To investigate enzyme activity of CYP1A1, relevant enzyme activities were assessed through the CYP1A1-specific deethylation of ethoxyresorufin [26], as shown in Fig. 2. Microsomes from hepatic tissues of rats exposed to high dose of caffeine (100 mg/kg b.w./day) showed a statistically significant increase in EROD activity in relation to control (3.1-fold). In contrast, high dose of CMGE (2000 mg/kg b.w./day) did not cause a similar induction of activity in relation to control. "
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    ABSTRACT: Chios mastic gum (CMG), a resin derived from Pistacia lentiscus var. chia, is known since ancient times for its pharmacological activities. CYP1A1 and CYP1A2 enzymes are among the most involved in the biotransformation of chemicals and the metabolic activation of pro-carcinogens. Previous studies referring to the modulation of these enzymes by CMG have revealed findings of unclear biological and toxicological significance. For this purpose, the modulation of CYP1A1 and CYP1A2 enzymes in the liver of male Wistar rats following oral administration of CMG extract (CMGE), at the levels of mRNA and CYP1A1 enzyme activity, was compared to respective enzyme modulation following oral administration of a well-known bioactive natural product, caffeine, as control compound known to involve hepatic enzymes in its metabolism. mRNA levels of Cyp1a1 and Cyp1a2 were measured by reverse transcription real-time polymerase chain reaction and their relative quantification was calculated. CYP1A1 enzyme induction was measured through the activity of ethoxyresorufin-O-deethylase (EROD). The results indicated that administration of CMGE at the recommended pharmaceutical dose does not induce significant transcriptional modulation of Cyp1a1/2 and subsequent enzyme activity induction of CYP1A1 while effects of the same order of magnitude were observed in the same test system following the administration of caffeine at the mean daily consumed levels. The outcome of this study further confirms the lack of any toxicological or biological significance of the specific findings on liver following the administration of CMGE.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "Enan (2001) suggested that the toxicity of essential oil constituents is related to the octopaminergic nervous system of the insects. On the other hand, De Oliveira et al. (1997) mentioned that some monoterpenes may inhibit cytochrome P-450-dependent monooxygenases (De Oliveira et al. 1997 "
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    • "Liver microsomal fraction I (MF I) was prepared as described previously [20], except for the use of 100 mM Tris 150 mM KCl buffer solution pH 7.4 instead of the sucrose solution. Aliquots of MF I were stored at -80°C until further use. "
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