Bioflavonoids: selective substrates and inhibitors for cytochrome P450 CYP1A and CYP1B1.
TL;DR: Hydroxy and/or methoxy substitutions at the 3' and 4' positions in the flavonoid structures were the major factors involved in conveying selectivity for the different cytochrome P450 enzymes.
About: This article is published in Toxicology.The article was published on 2000-04-03. It has received 273 citations till now. The article focuses on the topics: Eriodictyol & Homoeriodictyol.
Citations
More filters
TL;DR: The diversity and multiple mechanisms of flavonoid action, together with the numerous methods of initiation, detection and measurement of oxidative processes in vitro and in vivo offer plausible explanations for existing discrepancies in structure-activity relationships.
Abstract: Flavonoids are a class of secondary plant phenolics with significant antioxidant and chelating properties. In the human diet, they are most concentrated in fruits, vegetables, wines, teas and cocoa. Their cardioprotective effects stem from the ability to inhibit lipid peroxidation, chelate redox-active metals, and attenuate other processes involving reactive oxygen species. Flavonoids occur in foods primarily as glycosides and polymers that are degraded to variable extents in the digestive tract. Although metabolism of these compounds remains elusive, enteric absorption occurs sufficiently to reduce plasma indices of oxidant status. The propensity of a flavonoid to inhibit free-radical mediated events is governed by its chemical structure. Since these compounds are based on the flavan nucleus, the number, positions, and types of substitutions influence radical scavenging and chelating activity. The diversity and multiple mechanisms of flavonoid action, together with the numerous methods of initiation, detection and measurement of oxidative processes in vitro and in vivo offer plausible explanations for existing discrepancies in structure-activity relationships. Despite some inconsistent lines of evidence, several structure-activity relationships are well established in vitro. Multiple hydroxyl groups confer upon the molecule substantial antioxidant, chelating and prooxidant activity. Methoxy groups introduce unfavorable steric effects and increase lipophilicity and membrane partitioning. A double bond and carbonyl function in the heterocycle or polymerization of the nuclear structure increases activity by affording a more stable flavonoid radical through conjugation and electron delocalization. Further investigation of the metabolism of these phytochemicals is justified to extend structure-activity relationships (SAR) to preventive and therapeutic nutritional strategies.
3,567 citations
TL;DR: Evidence for the structural promiscuity of AhR ligand binding is described and the current state of knowledge with regards to the activation of the AhR signaling pathway by naturally occurring exogenous and endogenous ligands is discussed.
Abstract: The induction of expression of genes for xenobiotic metabolizing enzymes in response to chemical insult is an adaptive response found in most organisms. In vertebrates, the AhR is one of several chemical/ligand-dependent intracellular receptors that can stimulate gene transcription in response to xenobiotics. The ability of the AhR to bind and be activated by a range of structurally divergent chemicals suggests that the AhR contains a rather promiscuous ligand binding site. In addition to synthetic and environmental chemicals, numerous naturally occurring dietary and endogenous AhR ligands have also been identified. In this review, we describe evidence for the structural promiscuity of AhR ligand binding and discuss the current state of knowledge with regards to the activation of the AhR signaling pathway by naturally occurring exogenous and endogenous ligands.
1,716 citations
Cites background from "Bioflavonoids: selective substrates..."
...In addition to interacting with the AhR, many of these flavonoids are also substrates for CYP1A1 (51)....
[...]
TL;DR: The current knowledge regarding potential dietary flavonoid/phenolic-induced toxicity concerns, including their pro-oxidant activity, mitochondrial toxicity (potential apoptosis-inducing properties), and interactions with drug-metabolizing enzymes are summarized.
1,001 citations
TL;DR: The cancer protective effects of flavonoids have been attributed to a wide variety of mechanisms, including modulating enzyme activities resulting in the decreased carcinogenicity of xenobiotics and phase II enzymes, largely responsible for the detoxification of carcinogens.
834 citations
TL;DR: This chapter is an update of the data on substrates, reactions, inducers, and inhibitors of human CYP enzymes published previously by Rendic and DiCarlo, now covering selection of the literature through 2001 in the reference section.
Abstract: This chapter is an update of the data on substrates, reactions, inducers, and inhibitors of human CYP enzymes published previously by Rendic and DiCarlo (1), now covering selection of the literature through 2001 in the reference section. The data are presented in a tabular form (Table 1) to provide a framework for predicting and interpreting the new P450 metabolic data. The data are formatted in an Excel format as most suitable for off-line searching and management of the Web-database. The data are presented as stated by the author(s) and in the case when several references are cited the data are presented according to the latest published information. The searchable database is available either as an Excel file (for information contact the author), or as a Web-searchable database (Human P450 Metabolism Database, www.gentest.com) enabling the readers easy and quick approach to the latest updates on human CYP metabolic reactions.
788 citations
References
More filters
TL;DR: This revision supersedes the four previous updates in which a nomenclature system, based on divergent evolution of the P450 superfamily has been described and is similar to that proposed in the previous updates.
Abstract: We provide here a list of 481 P450 genes and 22 pseudogenes, plus all accession numbers that have been reported as of October 18,1995. These genes have been described in 85 eukaryote (including vertebrates, invertebrates, fungi, and plants) and 20 prokaryote species. Of 74 gene families so far descr
2,888 citations
Journal Article•
TL;DR: The selectivity of this enzyme in the activation of a variety of environmental carcinogens and mutagens in Salmonella typhimurium TA1535/pSK1002 or NM2009 tester strains was examined using the SOS response as an end point of DNA damage.
Abstract: A human cytochrome P-450 (P450) 1B1 cDNA was expressed in Saccharomyces cerevisiae , and the microsomes containing P450 1B1 were used to examine the selectivity of this enzyme in the activation of a variety of environmental carcinogens and mutagens in Salmonella typhimurium TA1535/pSK1002 or NM2009 tester strains, using the SOS response as an end point of DNA damage. We also determined and compared these activities of P450 1B1 with those catalyzed by recombinant human P450s 1A1 and 1A2, which were purified from membranes of Escherichia coli . The carcinogenic chemicals tested included 27 polycyclic aromatic hydrocarbons and their dihydrodiol derivatives, 17 heterocyclic and aryl amines and aminoazo dyes, three mycotoxins, two nitroaromatic hydrocarbons, N -nitrosodimethylamine, vinyl carbamate, and acrylonitrile. Among the three P450 enzymes examined here, P450 1B1 was found to have the highest catalytic activities for the activation of 11,12-dihydroxy-11,12-dihydrodibenzo[ a,l ]pyrene, 1,2-dihydroxy-1,2-dihydro-5-methylchrysene, (+)-7,8-dihydroxy-7,8-dihydrobenzo[ a ]pyrene, 11,12-dihydroxy-11,12-dihydrobenzo[ g ]chrysene, 3,4-dihydroxy-3,4-dihydrobenzo[ c ]phenanthrene, 3-amino-1,4-dimethyl-5 H -pyrido[4,3- b ]indole, 2-aminoanthracene, 3-methoxy-4-aminoazobenzene, and 2-nitropyrene. P450 1B1 also catalyzed the activation of 2-amino-3,5-dimethylimidazo[4,5- f ]quinoline, 2-amino-3,8-dimethylimidazo[4,5- f ]quinoxaline, 2-amino-3-methylimidazo[4,5- f ]quinoline, 2-aminofluorene, 6-aminochrysene and its 1,2-dihydrodiol, (-)-7,8-dihydroxy-7,8-dihydrobenzo[ a ]pyrene, 1,2-dihydroxy-1,2-dihydrochrysene, 1,2-dihydroxy-1,2-dihydro-5,6-dimethylchrysene, 2,3-dihydroxy-2,3-dihydrofluoranthene, 3,4-dihydroxy-3,4-dihydro-7,12-dimethylbenz[ a ]anthracene, and 6-nitrochrysene to appreciable extents. However, P450 1B1 did not produce genotoxic products from benzo[ a ]pyrene, trans -3,4-dihydroxy-3,4-dihydrobenzo[ a ]anthracene, trans -8,9-dihydroxy-8,9-dihydrobenzo[ a ]anthracene, 7,12-dimethylbenz[ a ]anthracene and its cis -5,6-dihydrodiol, 5-methylchrysene, 11,12-dihydroxy-11,12-dihydro-3-methylcholanthrene, 1,2-dihydroxy-1,2-dihydro-6-methylchrysene, benzo[ c ]phenanthrene, 2-amino-6-methyldipyrido[1,2- a :3′,2′- d ]imidazole, 2-acetylaminofluorene, benzidine, 2-naphthylamine, aflatoxin B 1 , aflatoxin G 1 , sterigmatocystin, N -nitrosodimethylamine, vinyl carbamate, or acrylonitrile in this assay system. P450 1B1 is expressed constitutively in extrahepatic organs, including fetal tissue samples, and is highly inducible in various organs by 2,3,7,8-tetrachlorodibenzo- p -dioxin and related compounds in experimental animal models. Thus, activation of procarcinogens by P450 1B1 may contribute to human tumors of extrahepatic origin.
791 citations
TL;DR: Rat liver microsomal AROD results show that ratios between different alkoxyresorufin O-dealkylation (AROD) activities can be more useful than absolute values of single activities for identifying P450 forms.
551 citations
"Bioflavonoids: selective substrates..." refers methods in this paper
..., methoxy-, ethoxy-, propoxy-, butoxy-, and benzyloxyresorufin) were determined using continuous fluorimetry with NADPH as cofactor (Burke et al., 1994)....
[...]
Journal Article•
TL;DR: The results provide the basis for the development of novel methods of cancer diagnosis based on the identification of CYP1B1 in tumor cells and thedevelopment of anticancer drugs that are selectively activated in tumors by CYP 1B1.
Abstract: Cytochrome P450 CYP1B1 is a recently cloned dioxin-inducible form of the cytochrome P450 family of xenobiotic metabolizing enzymes. An antibody raised against a peptide specific for CYP1B1 was found to recognize CYP1B1 expressed in human lymphoblastoid cells but not to recognize other forms of cytochrome P450, particularly CYP1A1 and CYP1A2. Using this antibody, the cellular distribution and localization of CYP1B1 were investigated by immunohistochemistry in a range of malignant tumors and corresponding normal tissues. CYP1B1 was found to be expressed at a high frequency in a wide range of human cancers of different histogenetic types, including cancers of the breast, colon, lung, esophagus, skin, lymph node, brain, and testis. There was no detectable immunostaining for CYP1B1 in normal tissues. These results provide the basis for the development of novel methods of cancer diagnosis based on the identification of CYP1B1 in tumor cells and the development of anticancer drugs that are selectively activated in tumors by CYP1B1.
530 citations
"Bioflavonoids: selective substrates..." refers background in this paper
..., 1998), the CYP1B1 protein has only been detected in cancer cells (McKay et al., 1995; Murray et al., 1997)....
[...]
TL;DR: The results indicate that CYP1B1 is expressed in many normal human tissues and advance the understanding of the complexity of a gene family of cytochromes P450 whose expression is altered by TCDD.
514 citations