Comparative induction of unscheduled DNA synthesis in cultured rat hepatocytes by allylbenzenes and their 1′-hydroxy metabolites

Chan, Vicky; Caldwell, John

doi:10.1016/0278-6915(92)90047-o

Cited by 72 publications

(44 citation statements)

References 13 publications

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“…Human CYP1A2 and CYP2C9 are the major enzymes responsible for conversion of methyleugenol to 1'-hydroxymethyleugenol, with CYP2D6 and 2C19 being lesser important for 1'-hydroxylation of methyleugenol [1135,1136]. Methyleugenol, 1'-hydroxymethyleugenol and methyleugenol-2',3'-oxide induce unscheduled DNA synthesis in cultured rat hepatocytes [1137], which is correlated with carcinogenicity in rodents [1138,1139]. In addition, methyleugenol has been shown to form adducts with DNA and protein in human fibroblasts V79 cells transfected with human genes expressing sulfotransferases and in the mouse liver in vivo [1140].…”

Section: Alkenylbenzenesmentioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

149

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Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

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Section: Alkenylbenzenesmentioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

149

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“…Estragole is consistently found to induce liver DNA damage, but evidence of genetic damage has been less consistent. Estragole and 1‐hydroxy metabolites induced a dose‐related increase in unscheduled DNA synthesis (UDS) in cultured F344 rat hepatocytes [Chan and Caldwell, ] and DNA adducts in livers of mice [Phillips et al, ; Randerath et al, ]. No induction of peripheral blood micronuclei (PBMN) was observed in peripheral blood of male or female mice [NTP, ].…”

Section: Introductionmentioning

confidence: 99%

In vivo genotoxicity of estragole in male F344 rats

Ding

Levy

Bishop

et al. 2014

Environ and Mol Mutagen

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Estragole, a naturally occurring constituent of various herbs and spices, is a rodent liver carcinogen which requires bio-activation. To further understand the mechanisms underlying its carcinogenicity, genotoxicity was assessed in F344 rats using the comet, micronucleus (MN), and DNA adduct assays together with histopathological analysis. Oxidative damage was measured using human 8-oxoguanine-DNA-N-glycosylase (hOGG1) and EndonucleaseIII (EndoIII)-modified comet assays. Results with estragole were compared with the structurally related genotoxic carcinogen, safrole. Groups of seven-week-old male F344 rats received corn oil or corn oil containing 300, 600, or 1,000 mg/kg bw estragole and 125, 250, or 450 mg/kg bw safrole by gavage at 0, 24, and 45 hr and terminated at 48 hr. Estragole-induced dose-dependent increases in DNA damage following EndoIII or hOGG1 digestion and without enzyme treatment in liver, the cancer target organ. No DNA damage was detected in stomach, the non-target tissue for cancer. No elevation of MN was observed in reticulocytes sampled from peripheral blood. Comet assays, both without digestion or with either EndoIII or hOGG1 digestion, also detected DNA damage in the liver of safrole-dosed rats. No DNA damage was detected in stomach, nor was MN elevated in peripheral blood following dosing with safrole suggesting that, as far both safrole and estragole, oxidative damage may contribute to genotoxicity. Taken together, these results implicate multiple mechanisms of estragole genotoxicity. DNA damage arises from chemical-specific interaction and is also mediated by oxidative species.

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“…In addition, especially at higher doses, neuroendocrine tumors of the glandular stomach, as well as renal tube hyperplasia and adenomas were observed. In vitro, methyleugenol as well as its metabolites 19-hydroxymethyleugenol and methyleugenol-29,39-oxide induce unscheduled DNA synthesis (UDS) in cultured rat hepatocytes [82]. Howes et al [83] reported an excellent correlation between UDS induction in rat hepatocytes and results from rodent carcinogenicity studies for methyleugenol and also for related alkenylbenzenes like estragole and safrole.…”

Section: Mechanism Of Toxic Actionmentioning

confidence: 97%

Molecular mechanisms of toxicity of important food-borne phytotoxins

Rietjens¹,

Martena

Boersma

et al. 2005

Mol. Nutr. Food Res.

103

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At present, there is an increasing interest for plant ingredients and their use in drugs, for teas, or in food supplements. The present review describes the nature and mechanism of action of the phytochemicals presently receiving increased attention in the field of food toxicology. This relates to compounds including aristolochic acids, pyrrolizidine alkaloids, beta-carotene, coumarin, the alkenylbenzenes safrole, methyleugenol and estragole, ephedrine alkaloids and synephrine, kavalactones, anisatin, St. John's wort ingredients, cyanogenic glycosides, solanine and chaconine, thujone, and glycyrrhizinic acid. It can be concluded that several of these phytotoxins cause concern, because of their bioactivation to reactive alkylating intermediates that are able to react with cellular macromolecules causing cellular toxicity, and, upon their reaction with DNA, genotoxicity resulting in tumors. Another group of the phytotoxins presented is active without the requirement for bioactivation and, in most cases, these compounds appear to act as neurotoxins interacting with one of the neurotransmitter systems. Altogether, the examples presented illustrate that natural does not equal safe and that in modern society adverse health effects, upon either acute or chronic exposure to phytochemicals, can occur as a result of use of plant- or herb-based foods, teas, or other extracts.

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Comparative induction of unscheduled DNA synthesis in cultured rat hepatocytes by allylbenzenes and their 1′-hydroxy metabolites

Cited by 72 publications

References 13 publications

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

In vivo genotoxicity of estragole in male F344 rats

Molecular mechanisms of toxicity of important food-borne phytotoxins

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