A high-performance liquid chromatography assay for measuring integrated biphenyl metabolism by intact cells: Its use with rat liver and human liver and kidney

Powis, Garth; Moore, D. J.; Wilke, Tracy J.; Santone, Kenneth S.

doi:10.1016/0003-2697(87)90151-5

Cited by 21 publications

(8 citation statements)

References 15 publications

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“…The formation of the 2,3,4-trihydroxybenzophenone metabolite is mainly catalyzed by CYP2D6 activity in humans, and it is unclear why the software missed it as a potential metabolite of benzophenone 3. Diphenyl metabolism is induced via CYP1 A /2B reactions, and while 3-hydroxydiphenyl has been identified as a liver microsomal oxidation product in several mammals, it has not yet been detected in human-derived samples . It is possible that human CYP isoforms are unable to catalyze the C3 regio-specific hydroxylation of diphenyl or that the software only predicts para-hydroxylation of aryl moieties, as CYP-catalyzed meta- and ortho-hydroxylations occur less frequently .…”

Section: Discussionmentioning

confidence: 99%

“…Diphenyl metabolism is induced via CYP1A/2B reactions, and while 3hydroxydiphenyl has been identified as a liver microsomal oxidation product in several mammals, 55 it has not yet been detected in human-derived samples. 56 It is possible that human CYP isoforms are unable to catalyze the C3 regio-specific hydroxylation of diphenyl or that the software only predicts parahydroxylation of aryl moieties, as CYP-catalyzed meta-and ortho-hydroxylations occur less frequently. 57 Additionally, metabolites with potential endocrine activity derived from extra-hepatic metabolism, such as the prostaglandin H synthase system or from gut microbiota reactions, will not likely be predicted by the model.…”

Section: Chemical Research In Toxicologymentioning

confidence: 99%

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Prediction of Estrogenic Bioactivity of Environmental Chemical Metabolites

Pinto

Mansouri

Judson

et al. 2016

Chem. Res. Toxicol.

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The US Environmental Protection Agency's (EPA) Endocrine Disruptor Screening Program (EDSP) is using in vitro data generated from ToxCast/Tox21 high-throughput screening assays to assess the endocrine activity of environmental chemicals. Considering that in vitro assays may have limited metabolic capacity, inactive chemicals that are biotransformed into metabolites with endocrine bioactivity may be missed for further screening and testing. Therefore, there is a value in developing novel approaches to account for metabolism and endocrine activity of both parent chemicals and their associated metabolites. We used commercially available software to predict metabolites of 50 parent compounds, out of which 38 chemicals are known to have estrogenic metabolites, and 12 compounds and their metabolites are negative for estrogenic activity. Three ER QSAR models were used to determine potential estrogen bioactivity of the parent compounds and predicted metabolites, the outputs of the models were averaged, and the chemicals were then ranked based on the total estrogenicity of the parent chemical and metabolites. The metabolite prediction software correctly identified known estrogenic metabolites for 26 out of 27 parent chemicals with associated metabolite data, and 39 out of 46 estrogenic metabolites were predicted as potential biotransformation products derived from the parent chemical. The QSAR models estimated stronger estrogenic activity for the majority of the known estrogenic metabolites compared to their parent chemicals. Finally, the three models identified a similar set of parent compounds as top ranked chemicals based on the estrogenicity of putative metabolites. This proposed in silico approach is an inexpensive and rapid strategy for the detection of chemicals with estrogenic metabolites and may reduce potential false negative results from in vitro assays.

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Section: Discussionmentioning

confidence: 99%

Section: Chemical Research In Toxicologymentioning

confidence: 99%

Prediction of Estrogenic Bioactivity of Environmental Chemical Metabolites

Pinto

Mansouri

Judson

et al. 2016

Chem. Res. Toxicol.

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“…Among these chemicals, biphenyl is commonly used as a synthetic resin, as a heat transfer medium in manufacturing, and as a fungistatic agent for preserving fresh citrus fruits (11); the calculi induced by biphenyl are composed of its metabolites, such as 4-hydroxybiphenyl-o-sulfate (4-HBPOS) 1 (12), whereas the calculi induced by each of the other chemicals mentioned above are composed of themselves instead of their metabolites. In relation to these features, it should be noted that numerous studies on the metabolism of biphenyl have been reported (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Biphenyl is metabolized via multiple pathways, resulting in the production of various derivatives such as conjugates (sulfate and glucuronide) of 4-hydroxybiphenyl (4-HBP) and 4,4′-dihydroxybiphenyl (4,4′-DHBP) produced as major metabolites and conjugates of 2-hydroxybiphenyl (2-HBP), 3-hydroxybiphenyl (3-HBP), and 3,4-dihydroxybiphenyl (3,4-DHBP) produced as minor metabolites, but only the sulfate conjugate of 4-HBP is significantly involved in the formation of urinary calculi (12).…”

Section: Introductionmentioning

confidence: 99%

Sex Dependence of the Components and Structure of Urinary Calculi Induced by Biphenyl Administration in Rats

Ohnishi

Yajima

Yamamoto

et al. 2000

Chem. Res. Toxicol.

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To obtain definitive information about the mechanisms of urinary calculus formation and the structural characteristics of the calculi induced by biphenyl administration in rats, with a focus on the sex dependency, the constituents of the urinary calculi were analyzed by HPLC, inductively coupled plasma spectroscopy (ICP), micro Fourier transform infrared spectroscopy (mFT-IR), and ion chromatography (IC), and structural analyses were carried out by microscopy, mFT-IR, and the electron probe microanalyzer (EPMA) method. We attempted to account for the appreciably higher incidence of calculi in males than in females. mFT-IR analysis revealed that the biphenyl-induced urinary calculi in male rats are composed mainly of potassium 4-hydroxybiphenyl-o-sulfate (4-HBPOSK), whereas the calculi in female rats are composed mainly of 4-hydroxybiphenyl (4-HBP) and KHSO(4) produced by the hydrolysis of 4-HBPOSK. Observations of photomicrographs and the results of mFT-IR analysis indicated that the calculi in males have a multilayer structure consisting of alternating layers of 4-HBPOSK and calcium phosphate, whereas the calculi in females have no multilayer structure, but open holes in which needle-shaped crystals are present in some places. In view of the results of these analyses, including the EPMA analysis, it appears that calculus formation in males may involve a series of successive and irreversible reactions, whereas calculus formation in females may result from a series of reversible reactions, including the hydrolysis of 4-HBPOSK. It was inferred that the series of irreversible reactions involved in calculus formation in males is relatively more stable than that in the case of females, and thus, a sex difference in the reaction features may be responsible for the observed difference in the incidence of calculus formation.

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“…4-Hydroxydiphenyl glucuronide and sulfate were reported to be formed by rat hepatocytes, or liver and kidney slices. 25,26) In the present study, we showed that DP, DPM and DPP are oxidized to the 4-hydroxyl derivatives, and in the case of DP to the 2-, and 3-hydroxyl derivatives as well, by cytochrome P450 of rat liver microsomes, and the 4,4′-dihydroxyl derivatives are also formed as minor metabolites. These microsomal oxidations were stimulated by the pretreatment of rats with 3-MC or phenobarbital.…”

Section: Discussionmentioning

confidence: 86%

Metabolic Activation of Proestrogenic Diphenyl and Related Compounds by Rat Liver Microsomes

Kawa

Sanoh

Kohta

et al. 2003

JOURNAL OF HEALTH SCIENCE

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In this study, liver microsome-mediated activation of diphenyl (DP), diphenylmethane (DPM) and 2,2-diphenylpropane (DPP) to estrogens was demonstrated. These three compounds were negative in estrogen reporter assay using estrogen-responsive human breast cancer cell line MCF-7. However, they exhibited estrogenic activity after incubation with liver microsomes of 3-methylcholanthrene-treated rats in the cases of DP and DPM, or of phenobarbital-treated rats in the cases of DP and DPP, in the presence of NADPH. When these compounds were incubated with liver microsomes in the presence of NADPH, monohydroxyl and dihydroxyl derivatives were formed. These hydroxylated metabolites, 4-hydroxydiphenyl, 3-hydroxydiphenyl, 2-hydroxydiphenyl, 4-hydroxydiphenylmethane, 2-(4-hydroxyphenyl)-2-phenylpropane (4-OH-DPP), 4,4′-dihydroxydiphenyl, 4,4′-dihydroxydiphenylmethane and 2,2-bis(4-hydroxyphenyl)propane (bisphenol A), all exhibited estrogenic activity in MCF-7 cells. Binding assay of these hydroxylated compounds with rat uterus estrogen receptor was also positive. These results suggest that the estrogenic activities of DP, DPM and DPP were due to the formation of hydroxylated metabolites by the liver cytochrome P450 system.Key words ---diphenyl, estrogenic activity, metabolic activation, human breast cancer cell line MCF-7, endocrine disruption, cytochrome P450 exert biological effects. Many so-called xenoestrogens produce a wide variety of toxic effects in animals. They may be playing a role in the increasing incidence of hormonally related cancers such as breast cancer and testicular cancer, and other problems of the reproductive system in humans. It is therefore important to screen environmental contaminants for estrogenic activity. Their metabolites also need to be identified and screened. We recently showed that trans-stilbene, which is the parent compound of diethylstilbestrol, and trans-stilbene oxide were not estrogenic, but exhibited a potent estrogenic activity after metabolic activation by a liver microsomal oxidation system. 4,5) In that report, we suggested that the estrogenic activity was due to the hydroxylated metabolites, trans-4-hydroxystilbene and trans-4,4′-dihydroxystilbene, formed by cytochrome P450 1A1/2. Furthermore, we demonstrated that styrene oligomers were metabolically activated to estrogens by rat liver microsomes, especially cytochrome P450 2B1.6) These results demonstrate the importance of considering proestrogenic potential, when screening for xenoestrogens in the environment.

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A high-performance liquid chromatography assay for measuring integrated biphenyl metabolism by intact cells: Its use with rat liver and human liver and kidney

Cited by 21 publications

References 15 publications

Prediction of Estrogenic Bioactivity of Environmental Chemical Metabolites

Prediction of Estrogenic Bioactivity of Environmental Chemical Metabolites

Sex Dependence of the Components and Structure of Urinary Calculi Induced by Biphenyl Administration in Rats

Metabolic Activation of Proestrogenic Diphenyl and Related Compounds by Rat Liver Microsomes

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