Basil extract inhibits the sulfotransferase mediated formation of DNA adducts of the procarcinogen 1'-hydroxyestragole by rat and human liver S9 homogenates and in HepG2 human hepatoma cells.

The effects of a basil extract on the sulfation and concomitant DNA adduct formation of the proximate carcinogen 1'-hydroxyestragole were studied using rat and human liver S9 homogenates and the human hepatoma cell line HepG2. Basil was chosen since it contains the procarcinogen estragole that can be metabolized to 1'-hydroxyestragole by cytochrome P450 enzymes. Basil extract addition to incubations of rat and human liver S9 homogenates with 1'-hydroxyestragole, the sulfotransferase cofactor PAPS, and 2'-deoxyguanosine resulted in a dose-dependent inhibition of N2-(trans-isoestragol-3'-yl)-2'-deoxyguanosine formation. Because the inhibition resembled the inhibition by the sulfotransferase inhibitor pentachlorophenol and since the inhibition was not observed in incubations with the direct electrophile 1'-acetoxyestragole it is concluded that the inhibition occurs at the level of the sulfotransferase mediated bioactivation step. Additional experiments in HepG2 cells revealed the same protective effect of basil extract in intact cells, demonstrating that the inhibitors are able to enter the cells. The results of this study suggest that bioactivation and subsequent adverse effects of 1'-hydroxyestragole might be lower in a matrix of other basil ingredients than what would be expected on the basis of experiments using 1'-hydroxyestragole as a single compound.

[1]  T. Mosmann.  Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[2]  E. Sudhölter,et al.  Development of an on-line high performance liquid chromatography detection system for human cytochrome P450 1A2 inhibitors in extracts of natural products. , 2007, Journal of chromatography. A.

[3]  Jos H Beijnen,et al.  An update on in vitro test methods in human hepatic drug biotransformation research: pros and cons. , 2003, Toxicology and applied pharmacology.

[4]  L. Iyer,et al.  Glucuronidation of 1'-hydroxyestragole (1'-HE) by human UDP-glucuronosyltransferases UGT2B7 and UGT1A9. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[5]  M. Silano,et al.  Constituents of aromatic plants: I. Methyleugenol. , 2000, Fitoterapia.

[6]  I. Sipes,et al.  Cytotoxicity and genotoxicity of methyleugenol and related congeners-- a mechanism of activation for methyleugenol. , 2000, Mutation research.

[7]  P. van Bladeren,et al.  Human cytochrome p450 enzyme specificity for the bioactivation of estragole and related alkenylbenzenes. , 2007, Chemical research in toxicology.

[8]  Ivonne M C M Rietjens,et al.  Human cytochrome p450 enzymes of importance for the bioactivation of methyleugenol to the proximate carcinogen 1'-hydroxymethyleugenol. , 2006, Chemical research in toxicology.

[9]  G. Mulder,et al.  Inhibition of sulfate conjugation of N-hydroxy-2-acetylaminofluorene in isolated perfused rat liver and in the rat in vivo by pentachlorophenol and low sulfate. , 1980, Cancer research.

[10]  J. Miller,et al.  Major role of hepatic sulfotransferase activity in the metabolic activation, DNA adduct formation, and carcinogenicity of 1'-hydroxy-2',3'-dehydroestragole in infant male C57BL/6J x C3H/HeJ F1 mice. , 1985, Cancer research.

[11]  E C Miller,et al.  Further characterization of the DNA adducts formed by electrophilic esters of the hepatocarcinogens 1'-hydroxysafrole and 1'-hydroxyestragole in vitro and in mouse liver in vivo, including new adducts at C-8 and N-7 of guanine residues. , 1985, Cancer research.

[12]  E C Miller,et al.  Structure-activity studies of the carcinogenicities in the mouse and rat of some naturally occurring and synthetic alkenylbenzene derivatives related to safrole and estragole. , 1983, Cancer research.

[13]  E Solheim,et al.  Metabolism of alkenebenzene derivatives in the rat. I. p-Methoxyallylbenzene (Estragole) and p-methoxypropenylbenzene (Anethole). , 1973, Xenobiotica; the fate of foreign compounds in biological systems.

[14]  M Miele,et al.  Methyleugenol in Ocimum basilicum L. Cv. genovese gigante. , 2001, Journal of agricultural and food chemistry.

[15]  E C Miller,et al.  Structures of the DNA adducts formed in mouse liver after administration of the proximate hepatocarcinogen 1'-hydroxyestragole. , 1981, Cancer research.

[16]  E C Miller,et al.  Structure-activity studies of the hepatocarcinogenicities of alkenylbenzene derivatives related to estragole and safrole on administration to preweanling male C57BL/6J x C3H/HeJ F1 mice. , 1987, Cancer research.

[17]  E C Miller,et al.  Strong evidence from studies with brachymorphic mice and pentachlorophenol that 1'-sulfoöxysafrole is the major ultimate electrophilic and carcinogenic metabolite of 1'-hydroxysafrole in mouse liver. , 1983, Cancer research.

[18]  M. Delaforge,et al.  Biotransformation of allylbenzene analogues in vivo and in vitro through the epoxide-diol pathway. , 1980, Xenobiotica; the fate of foreign compounds in biological systems.

[19]  T. Guenthner,et al.  Hydrolysis of the 2',3'-allylic epoxides of allylbenzene, estragole, eugenol, and safrole by both microsomal and cytosolic epoxide hydrolases. , 1992, Drug metabolism and disposition: the biological fate of chemicals.

[20]  T. Guenthner,et al.  Investigation of the role of the 2',3'-epoxidation pathway in the bioactivation and genotoxicity of dietary allylbenzene analogs. , 2001, Toxicology.

[21]  P. Kasper,et al.  The genotoxic potential in vitro and in vivo of the allyl benzene etheric oils estragole, basil oil and trans-anethole. , 1994, Mutation research.

[22]  J I Goodman,et al.  Safety assessment of allylalkoxybenzene derivatives used as flavouring substances - methyl eugenol and estragole. , 2002, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[23]  J. Caldwell,et al.  Comparative induction of unscheduled DNA synthesis in cultured rat hepatocytes by allylbenzenes and their 1'-hydroxy metabolites. , 1992, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[24]  E C Miller,et al.  Hepatocarcinogenicity of estragole (1-allyl-4-methoxybenzene) and 1'-hydroxyestragole in the mouse and mutagenicity of 1'-acetoxyestragole in bacteria. , 1976, Journal of the National Cancer Institute.

[25]  G Williamson,et al.  Use of metabolically competent human hepatoma cells for the detection of mutagens and antimutagens. , 1998, Mutation research.

[26]  J. Schellens,et al.  Validation of in vitro cell models used in drug metabolism and transport studies; genotyping of cytochrome P450, phase II enzymes and drug transporter polymorphisms in the human hepatoma (HepG2), ovarian carcinoma (IGROV-1) and colon carcinoma (CaCo-2, LS180) cell lines. , 2006, Toxicology and applied pharmacology.

[27]  M. Silano,et al.  Constituents of aromatic plants: II. Estragole. , 2000, Fitoterapia.

[28]  A. Nouri,et al.  A new approach for measurement of cytotoxicity using colorimetric assay. , 1993, Journal of immunological methods.

[29]  Benoît Schilter,et al.  Tandem mass spectrometry analysis of N2-(trans-Isoestragol-3'-yl)-2'-deoxyguanosine as a strategy to study species differences in sulfotransferase conversion of the proximate carcinogen 1'-hydroxyestragole. , 2007, Chemical research in toxicology.