Author
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POULOSE, SHIBU - DEPT OF HORT SCI, TX A&M |
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Mayer, Richard |
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GIRENNAVAR, BASAVARAJ - DEPT OF HORT SCI, TX A&M |
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PIKE, LEONARD - DEPT OF HORT SCI, TX A&M |
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PATIL, BHIMANAGOUDA - DEPT OF HORT SCI, TX A&M |
Submitted to: Journal of Agricultural and Food Chemistry
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 10/28/2006 Publication Date: N/A Citation: N/A Interpretive Summary: Cytochrome P450 enzymes are known to play a vital role in the metabolic activation and detoxification of environmental toxic substances and drugs. Activation often results in the formation of reactive oxygen species, which consequently interact with DNA, leading to the etiology of cancer. Limonoids, a unique class of triterpinoids found in citrus fruits, were chromatographically isolated in pure form from seeds and molasses of citrus fruits. The effects of limonoid aglycones and glucosides on O-dealkylase and hydroxylase activities of human cytochrome P450 isoforms such as CYP1A2, CYP1B1, CYP3A4 and CYP19 were determined using ethoxyresorufin, methoxyresorufin, and dibenzylfluorescein as substrates. Significant (P < 0.001) reductions in enzyme activities were observed with concentrations as low as 0.5 uM for glycosides and 2 uM for aglycones. Kinetic analyses indicated that limonin 17b-D glucopyranoside (LG) inhibited CYP19 competitively, while nomilinic acid 17b-D glucopyranoside (NAG) inhibited CYP19 in a noncompetitive fashion. Inhibitory effects of LG were reversible with increasing concentration of DBF, while non-reversible for NAG. The IC50 values were found to be much lower for limonoid glucosides (< 10 uM), when compared to limonoid aglycones (10-30 uM). Acidic limonoid glucosides were found to be the better inhibitors of cytochrome P450 enzymes than were non-acidic glucosides and limonoid aglycones, suggesting a role for specific functional groups in the inhibition kinetics. While structural variations of the limonoid molecule can be ascribed to the differences in efficacy, our results suggest citrus limonoids act as potential anticancer agents. Technical Abstract: Cytochrome P450 enzymes are known to play a vital role in the metabolic activation and detoxification of environmental toxic substances and drugs. Activation often results in the formation of reactive oxygen species, which consequently interact with DNA, leading to the etiology of cancer. Limonoids, a unique class of triterpinoids found in citrus fruits, were chromatographically isolated in pure form from seeds and molasses of citrus fruits. The effects of limonoid aglycones and glucosides on O-dealkylase and hydroxylase activities of human cytochrome P450 isoforms such as CYP1A2, CYP1B1, CYP3A4 and CYP19 were determined using ethoxyresorufin, methoxyresorufin, and dibenzylfluorescein as substrates. Significant (P < 0.001) reductions in enzyme activities were observed with concentrations as low as 0.5 uM for glycosides and 2 uM for aglycones. Kinetic analyses indicated that limonin 17b-D glucopyranoside (LG) inhibited CYP19 competitively, while nomilinic acid 17b-D glucopyranoside (NAG) inhibited CYP19 in a noncompetitive fashion. Inhibitory effects of LG were reversible with increasing concentration of DBF, while non-reversible for NAG. The IC50 values were found to be much lower for limonoid glucosides (< 10 uM), when compared to limonoid aglycones (10-30 uM). Acidic limonoid glucosides were found to be the better inhibitors of cytochrome P450 enzymes than were non-acidic glucosides and limonoid aglycones, suggesting a role for specific functional groups in the inhibition kinetics. While structural variations of the limonoid molecule can be ascribed to the differences in efficacy, our results suggest citrus limonoids act as potential anticancer agents. |