Apiaceous vegetable constituents inhibit human cytochrome P-450 1A2 (hCYP1A2) activity and hCYP1A2-mediated mutagenicity of aflatoxin B1

Peterson, Steven W.; Lampe, Johanna W.; Bammler, Theo K.; Gross-Steinmeyer, Kerstin; Eaton, David L.

doi:10.1016/j.fct.2006.04.010

Cited by 65 publications

(45 citation statements)

References 60 publications

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“…CYP1A2 is responsible for the metabolism of some drugs. CYP1A2 also reportedly metabolizes some naturally occurring chemicals and environmental contaminants and converts some of them to mutagenic and carcinogenic active metabolites, along with CYP1A1, which is mostly present in the lung (Peterson et al, 2006;Chang et al, 2013). Some well known examples are the biotransformation of polyaromatic hydrocarbons into their reactive metabolites that potentially cause DNA damage, leading to cancers (Lehr and Jerina, 1977).…”

Section: Discussionmentioning

confidence: 99%

“…Other compounds in this family, such as bergamottin, imperatorin, isoimperatorin, and trioxsalen, were reported to inhibit CYP3A4, CYP2D6, CYP2C19, CYP2E1, CYP2B6, rat cyp1a1, hCYP1A2, or P-glycoprotein (Baumgart et al, 2005;Paine et al, 2005;Iwanaga et al, 2010). PRN and IPRN have been reported to inhibit recombinant hCYP1A2 (Peterson et al, 2006;Kang et al, 2011). Apseloff et al (1990) reported that 8-methoxypsoralen was an inhibitor and inducer of theophylline metabolism in rats and an inhibitor in humans (induction was not studied).…”

Section: Introductionmentioning

confidence: 99%

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Identification and Characterization of Psoralen and Isopsoralen as Potent CYP1A2 Reversible and Time-Dependent Inhibitors in Human and Rat Preclinical Studies

et al. 2013

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Naturally occurring furanocoumarin compounds psoralen (PRN) and isopsoralen (IPRN) are bioactive constituents found in herbaceous plants. They are widely used as active ingredients in several Chinese herbal medicines. In this study, the CYP1A2 inhibitory potential of PRN and IPRN was investigated in rats in vitro and in vivo as well as in human liver microsomes. Both compounds exhibited reversible and time-dependent inhibition toward rat microsomal cyp1a2. The IC 50 , k inact , and K I values were 10.4 6 1.4 mM, 0.060 6 0.002 min 21 , and 1.13 6 0.12 mM for PRN, and 7.1 6 0.6 mM, 0.10 6 0.01 min 21 , and 1.95 6 0.31 mM for IPRN, respectively. In human liver microsomal incubations, potent reversible CYP1A2 inhibition was observed for both compounds, with IC 50 values of 0.26 6 0.01 mM and 0.22 6 0.03 mM for PRN and IPRN, respectively. However, time-dependent inhibition was only observed for IPRN, with k inact and K I values of 0.050 6 0.002 min 21 and 0.40 6 0.06 mM, respectively. Coadministration with PRN or IPRN significantly inhibited cyp1a2 activity in rats, with the area under the curve (AUC) of phenacetin increasing more than 5-fold. Simcyp simulation predicted that PRN would cause 1.71-and 2.12-fold increases in the phenacetin AUC in healthy volunteers and smokers, respectively. IPRN, on the other hand, would result in 3.24-and 5.01-fold increases in phenacetin AUCs in healthy volunteers and smokers, respectively. These findings represent the first detailed report comparing the potential drug-drug interactions of PRN and IPRN, and provide useful information for balancing safe and efficacious doses of PRN and IPRN.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification and Characterization of Psoralen and Isopsoralen as Potent CYP1A2 Reversible and Time-Dependent Inhibitors in Human and Rat Preclinical Studies

et al. 2013

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“…Along with glutathione S-transferases, mEH detoxifies electrophilic epoxides (EE) (5,6). These compounds are cytochrome P450 (CYP) derived mutagenic metabolites of tobacco-specific PAH, organic amines or fungeal aflatoxin (7). Microsomal EH hydrolizes the epoxides, generating water-soluble, less mutagenic, chemically less-active and excretable glycols.…”

Section: Introductionmentioning

confidence: 99%

EPHX1 polymorphisms do not modify esophageal carcinoma susceptibility in Dutch Caucasians

et al. 2012

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Abstract. Esophageal cancer (EC) has a globally increasing incidence with poor curative treatment options and survival rates. Crucial risk factors are exposure to toxins or carcinogens. Microsomal epoxide hydrolase (mEH) is a biotransformation enzyme essential for the detoxification of xenobiotics. Polymorphisms in exon 3 and exon 4 of the microsomal epoxide hydrolase gene (EPHX1) modify catalytic activity of this enzyme and subsequently may play a role in EC etiology. This case-control study investigated whether these polymorphisms in the EPHX1 gene influence esophageal cancer susceptibility in a Dutch Caucasian population. A case-control study including 349 Caucasian EC patients and 581 Caucasian healthy controls was conducted and the polymorphisms Tyr113His (exon 3) and His139Arg (exon 4) in the EPHX1 gene were determined, using polymerase chain reaction. The distribution of exon 3 and exon 4 genotypes were compared between cases and controls. Analyses included a stratification according to tumor histology; esophageal adenocarcinoma (EAC) or squamous cell carcinoma (ESCC). Furthermore, on the basis of allelic in vitro enzyme activity assays, exon 3 and 4 genotypes were combined and categorized according to their predicted high, medium or low enzyme activity. Homozygosity and heterozygosity for both exon 3 and 4 polymorphisms were correlated with a decreased esophageal squamous cell carcinoma risk. Heterozygosity and homozygosity for both polymorphisms correlated with an increased and a decreased esophageal adenocarcinoma risk, respectively. Predicted intermediate and high activity genotypes were risk and protective factors for esophageal squamous cell carcinoma and esophageal adenocarcinoma, respectively. However, none of these associations were statistically significant. In conclusion, the polymorphisms in exon 3 and exon 4 of the EPHX1 gene do not seem to be modifiers of esophageal squamous cell carcinoma or esophageal adenocarcinoma risk in Dutch Caucasians.

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“…These observations demonstrate that apigenin potently inhibits CYP1A2 in a binding mode similar to ANF, which is a potent inhibitor of CYP1A2 [16]. Recently, apigenin has been reported to inhibit CYP1A2 in a competitive manner [17] and to be hydroxylated to luteolin at the 3 -position of the B ring by CYP1A2 [18]. In addition to the docked apigenin conformation, these experimental data suggest that apigenin potently inhibits CYP1A2 by acting as a substrate inhibitor.…”

Section: Autodock Simulation Of Apigenin and Genistein For Cyp1a2mentioning

confidence: 72%

Differential mechanisms for the inhibition of human cytochrome P450 1A2 by apigenin and genistein

Shimada¹,

Eto²,

Ohtaguro³

et al. 2010

J Biochem & Molecular Tox

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The inhibitory effects of flavonoids on the human cytochrome P450 1A2 (CYP1A2) were examined. Among flavonoids tested, galangin, kaempferol, chrysin, and apigenin were potent inhibitors. Although apigenin belonging to flavones and genistein belonging to isoflavones are similar in the chemical structures, the inhibitory potencies for CYP1A2 were distinguished markedly between these two flavonoids. In computer-docking simulation, apigenin interacted with the same mode of cocrystallized alpha-naphthoflavone in the active site of CYP1A2, and then the B ring of apigenin was placed close to the heme iron of the enzyme with a single orientation. In contrast, the docked genistein conformation showed two different binding modes, and the A ring of genistein was oriented to the heme iron of CYP1A2. Furthermore, the binding free energy of apigenin was lower than that of genistein. These results demonstrate a possible mechanism that causes the differential inhibitory potencies of apigenin and genistein for CYP1A2.

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Apiaceous vegetable constituents inhibit human cytochrome P-450 1A2 (hCYP1A2) activity and hCYP1A2-mediated mutagenicity of aflatoxin B1

Cited by 65 publications

References 60 publications

Identification and Characterization of Psoralen and Isopsoralen as Potent CYP1A2 Reversible and Time-Dependent Inhibitors in Human and Rat Preclinical Studies

Identification and Characterization of Psoralen and Isopsoralen as Potent CYP1A2 Reversible and Time-Dependent Inhibitors in Human and Rat Preclinical Studies

EPHX1 polymorphisms do not modify esophageal carcinoma susceptibility in Dutch Caucasians

Differential mechanisms for the inhibition of human cytochrome P450 1A2 by apigenin and genistein

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