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At least 19 recordsLinked to original sources
PubMedDate not supplied

Modulation of the growth hormone-insulin-like growth factor (GH-IGF) axis by pharmaceutical, nutraceutical and environmental xenobiotics: an emerging role for xenobiotic-metabolizing enzymes and the transcription factors regulating their expression. A review.

The growth hormone-insulin-like growth factor (GH-IGF) axis has gained considerable focus over recent years. One cause of this increased interest is due to a correlation of age-related decline in plasma GH/IGF levels with age-related degenerative processes, and it has led to the prescribing of GH replacement therapy by some practitioners. On the other hand, however, research has also focused on the pro-carcinogenic effects of high GH-IGF levels, providing strong impetus for finding regimes that reduce its activity. Whereas the effects of GH/IGF activity on the action of xenobiotic-metabolizing enzyme systems is reasonably well appreciated, the effects of xenobiotic exposure on the GH-IGF axis has not received substantial review. Relevant xenobiotics are derived from pharmaceutical, nutraceutical and environmental exposure, and many of the mechanisms involved are highly complex in nature, not easily predictable from existing in vitro tests and do not always predict well from in vivo animal models. After a review of the human and animal in vivo and in vitro literature, a framework for considering the different levels of direct and indirect modulation by xenobiotics is developed herein, and areas that still require further investigation are highlighted, i.e. the actions of common endocrine disruptors such as pesticides and phytoestrogens, as well as the role of xenobiotic-metabolizing enzymes and the transcription factors regulating their expression. It is anticipated that a fuller appreciation of the existing human paradigms for GH-IGF axis modulation gained through this review may help explain some of the variation in levels of plasma IGF-1 and its binding proteins in the population, aid in the prescription of particular dietary regimens to certain individuals such as those with particular medical conditions, guide the direction of long-term drug/nutraceutical safety trials, and stimulate ideas for future research. It also serves to warn athletes that using compounds touted as performance enhancing because they promote short-term GH release could in fact be detrimental to performance in the long-run.

Dietary Supplements↗
PubMed2002

Identification of human hepatic cytochrome P450 sources of N-alkylprotoporphyrin IX after interaction with porphyrinogenic xenobiotics, implications for detection of xenobiotic-induced porphyria in humans.

Porphyrinogenicity of certain xenobiotics depends upon mechanism-based inactivation of specific cytochrome P450 (P450) enzymes, followed by formation of N-alkylprotoporphyrin IX (N-alkylPP). Examination of the porphyrinogenicity of xenobiotics in animals and extrapolation of the results to humans is associated with ambiguity due, in part, to differences between P450 enzymes. The goal of this study was to develop an in vitro test for the detection of N-alkylPPs, produced in human liver after administration of xenobiotics found to be porphyrinogenic in animals. This goal was achieved using fluorometry to detect N-alkylPP formation following mechanism-based inactivation by porphyrinogenic xenobiotics of single cDNA-expressed human P450 enzymes in microsomes prepared from baculovirus-infected insect cells (Supersomes) and in human liver microsomes. The following combinations of P450 enzymes were major sources of N-alkylPPs in Supersomes: CYP3A4 [3-[(arylthio)-ethyl]sydnone (TTMS)]; CYP1A2 and 2C9 [3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine (4-ethyl DDC)]; and CYP2C9, 2D6, and 3A4 [allylisopropylacetamide (AIA)]. Whereas similarities were found between results with human enzymes in Supersomes and their rat orthologs in rat liver microsomes, some differences were found. The results with TTMS and AIA, but not with 4-ethyl DDC, were the same in individual human enzymes expressed in Supersomes and human liver microsomes. We conclude that some differences exist between human liver P450 enzymes and their rat P450 orthologs in liver microsomes. It would therefore be prudent when dealing with xenobiotics in which porphyrinogenicity depends upon N-alkylPP formation to supplement animal data with studies using human P450 enzymes.

Animals↗
PubMed1998

[Interindividual differences in efficacy and toxicity induced by therapeutic drugs and xenobiotics in relation to genetic polymorphisms in xenobiotic metabolizing enzymes].

Humans incessantly ingest wide-variety of chemicals through the administration of therapeutic drugs, diets and beverages. Humans are also exposed to environmental mutagens and carcinogens and substances causing endocrine disruption. Metabolism and disposition have been regarded as one of the most important determinants of efficacy and toxicity induced by ingested chemicals, since remarkable individual difference was observed in the plasma concentration and/or urinary excretion after the administration of wide variety of therapeutic drugs such as isoniazid, sulfamethazine, debrisoquin, sparteine, mephenytoin and so on. This variability is resulted from pharmacogenetically regulated difference in the activities of xenobiotic metabolizing enzymes (so called genetic polymorphisms). Polymorphic appearance of xenobiotic metabolism has also been observed with various toxic substances such as ethanol, acetaldehyde, benzene, organic phosphates and environmental mutagens and carcinogens. Enzymes which show genetic polymorphisms include cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, CYP2C19, CYP2D6 and CYP2E1) and phase II drug metabolizing enzymes (arylamine N-acetyltransferases, glutathione S-transferases and UDP-glucuronosyl transferases). A number of mutations on the genes encoding polymorphic xenobiotic metabolizing enzymes have been associated with the remarkable individual difference in the metabolism and disposition in vivo. Individuals with distinct alleles of genes which encode defective enzymes have been shown to be at higher risk to toxic side effects by therapeutic drugs and more susceptible to certain malignant diseases. Research has to be conducted for each human race concerning risk assessment of chemicals, since ethnic differences in frequency of distinct alleles of genes encoding xenobiotic metabolizing enzymes are reported. In case of type 1 Crigler-Najjar syndrome causing unconjugated hyperbilirubinemia, complete loss of bilirubin-detoxifing UDP-glucuronosyl transferase has been attributed to nonsense, missense, and/or frameshift mutations that occurred at various sites on UGT1 gene. Thus, genetic polymorphisms of xenobiotic metabolizing enzymes are one of the most important factors influencing efficacy of therapeutic drugs and toxicity by wide-variety of chemicals.

Alleles↗
PubMed2001

Conservation of signaling pathways of xenobiotic-sensing orphan nuclear receptors, chicken xenobiotic receptor, constitutive androstane receptor, and pregnane X receptor, from birds to humans.

Chicken xenobiotic receptor, pregnane X receptor, and constitutive androstane receptor are orphan nuclear receptors that have recently been discovered to regulate drug- and steroid-mediated induction of hepatic cytochromes P450 (CYP). This induction is part of an adaptive response involving numerous genes to exposure to drugs and chemicals and has major clinical and toxicological implications. Here we report experiments in the chicken hepatoma cell line LMH that suggest evolutionary conservation of the signaling pathways triggered by pregnane X receptor, constitutive androstane receptor, and chicken xenobiotic receptor. Thus, the phenobarbital-inducible enhancer units of the mouse Cyp2b10, rat CYP2B2, and human CYP2B6 genes were activated in reporter gene assays by the same compounds that activate the chicken CYP2H1 phenobarbital-inducible enhancer units. Chicken xenobiotic receptor, pregnane X receptor, and constitutive androstane receptor all bound to the CYP2H1 phenobarbital-inducible enhancer units in gel-shift experiments. In CV-1 cell transactivation assays, mammalian pregnane X receptors activate the chicken phenobarbital-inducible enhancer units to the same extent as does chicken xenobiotic receptor, each receptor maintaining its species-specific ligand spectrum. To assess the reported role of protein phosphorylation in drug-mediated induction, we treated LMH cells with okadaic acid and observed increased mRNA of delta-aminolevulinate synthase and CYP2H1 whereas expression of CYP3A37 was decreased. The effects of okadaic acid and other modifiers of protein phosphorylation in LMH cells are comparable to those seen on CYP2Bs and CYP3As in mammalian primary hepatocyte cultures. These results indicate that closely related nuclear receptors, transcription factors, and signaling pathways are mediating the transcriptional activation of multiple genes by xenobiotics in chicken, rodents, and man.

Animals↗
PubMed2004

Mechanisms of cuticular uptake of xenobiotics into living plants: 1. Influence of xenobiotic dose on the uptake of three model compounds applied in the absence and presence of surfactants into Chenopodium album, Hedera helix and Stephanotis floribunda leaves.

This study determined the uptake of three model compounds, applied in the presence and absence of surfactants, into the leaves of three plant species (Chenopodium album L, Hedera helix L and Stephanotis floribunda Brongn). The results with 2-deoxy-D-glucose, 2,4-dichlorophenoxyacetic acid and epoxiconazole in the presence ofsurfactants (the polyethylene glycol monododecyl ethers C12EO3, C12EO6, C12EO10 and a trisiloxane ethoxylate with mean EO of 7.5, all used at one equimolar concentration and therefore different percentage concentrations) illustrate that the initial dose (nmol mm(-2)) of xenobiotic applied to plant foliage is a strong positive determinant of uptake. This held true for all the xenobiotics studied over a wide concentration range in the presence of these surfactants. Uptake on a unit area basis (nmol mm(-2)) could be related to the initial dose of xenobiotic applied per unit area (ID) by an equation of the form: Uptake = a [ID]b at time t = 24h. ID is given by the mass of xenobiotic applied, M divided by the droplet spread area, A. Total mass uptake is then calculated from an equation of the form: Total Uptake = a [ID]b x A.

2,4-Dichlorophenoxyacetic Acid↗
PubMed2006

Mutual repression between steroid and xenobiotic receptor and NF-kappaB signaling pathways links xenobiotic metabolism and inflammation.

While it has long been known that inflammation and infection reduce expression of hepatic cytochrome P450 (CYP) genes involved in xenobiotic metabolism and that exposure to xenobiotic chemicals can impair immune function, the molecular mechanisms underlying both of these phenomena have remained largely unknown. Here we show that activation of the nuclear steroid and xenobiotic receptor (SXR) by commonly used drugs in humans inhibits the activity of NF-kappaB, a key regulator of inflammation and the immune response. NF-kappaB target genes are upregulated and small bowel inflammation is significantly increased in mice lacking the SXR ortholog pregnane X receptor (PXR), thereby demonstrating a direct link between SXR and drug-mediated antagonism of NF-kappaB. Interestingly, NF-kappaB activation reciprocally inhibits SXR and its target genes whereas inhibition of NF-kappaB enhances SXR activity. This SXR/PXR-NF-kappaB axis provides a molecular explanation for the suppression of hepatic CYP mRNAs by inflammatory stimuli as well as the immunosuppressant effects of xenobiotics and SXR-responsive drugs. This mechanistic relationship has clinical consequences for individuals undergoing therapeutic exposure to the wide variety of drugs that are also SXR agonists.

Carcinoma, Hepatocellular↗
PubMed1991

Hepatic activities of xenobiotic metabolizing enzymes and biliary levels of xenobiotics in English sole (Parophrys vetulus) exposed to environmental contaminants.

English sole (Parophrys vetulus) are susceptible to the development of hepatic disease, including neoplasia, as a result of environmental exposure to polycyclic aromatic hydrocarbons (PAHs). The metabolism of PAHs, believed to be an essential factor in the development of neoplasia, has received considerable study in English sole, except that xenobiotic metabolizing enzymes (XMEs) have not been well-studied in this species. In the present work, the activities of hepatic aryl hydrocarbon hydroxylase (AHH), glutathione-S-transferase (GST), and epoxide hydrolase (EH) were measured in English sole exposed to several organic xenobiotics. These studies included an examination of the effects of captivity, the short-term responses of hepatic XME activities to several xenobiotic compounds, and detailed studies of the time- and dose-responses of hepatic XME activities to both a representative carcinogenic PAH (benzo[a]pyrene) and to a complex mixture of contaminants extracted from a sediment collected from a polluted area of Puget Sound, WA. Additionally, during the captivity and time- and dose-response studies, the levels of fluorescent aromatic compounds (FACs) were measured in the bile of the fish, both to provide an estimation of contaminant exposure and to evaluate the time- and dose-responses of this measure. The results of the captivity studies showed that the levels of FACs in bile were most affected by captivity, primarily as a result of changes in feeding status. The results of the exposure studies showed that xenobiotic metabolism, as reflected in hepatic activities of XMEs and levels of FACs in the bile, is altered by exposure to environmental contaminants. Whereas hepatic AHH activity could be rapidly and substantially increased by such exposure, activities of GST and EH were not affected, even up to 42 days after exposure. Moreover, because fish were exposed to a wide range of doses of chemicals or mixtures of chemicals which are known to be present in contaminated estuaries, and the responses of the hepatic AHH system and the levels of FACs in bile were measured at several time periods after exposure, the results provided substantial validation for the use of these two measures as bioindicators of exposure to environmental contamination in benthic fish.

Animals↗
PubMedDate not supplied

Cell responses to xenobiotics: comparison of MCF7 multi-drug- and mussel blood cell multi-xenobiotic-defense mechanisms.

Multi-drug resistance (MDR) in MCF7 breast cancer cells and multi-xenobiotic resistance (MXR) in mussel (Mytilus edulis) blood cells (MBC) are well known mechanisms that contribute to the decrease in intracellular concentrations of many unrelated but cytotoxic compounds. In the present work, we have carried out comparative investigations of the MDR/MXR protective mechanisms using a rapid colorimetric assay for cell viability and calcein accumulation for MDR/MXR activities. These studies were performed using cultured MCF7 and MBC before and after in vitro exposure to xenobiotics. Our results indicate that a 5-day exposure to doxorubicin or vincristine decreased calcein accumulation in MBC which is consistent with an induction of multi-xenobiotic resistance. The increase in calcein accumulation provoked by 1-h treatment with 50 microM verapamil was much lower in MBC when compared to the P-glycoprotein overexpressing MCF7 cell line. We conclude that such microplate assays could be used in primary cultures of MBC to estimate the effects of various chemicals on MXR activity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Effect of some indole derivatives on xenobiotic metabolism and xenobiotic-induced toxicity in cultured rat liver slices.

In this study the effect of some indole derivatives on xenobiotic metabolizing enzymes and xenobiotic-induced toxicity has been examined in cultured precision-cut liver slices from male Sprague-Dawley rats. While treatment of rat liver slices for 72 hours with 2-200 microM of either indole-3-carbinol (I3C) or indole-3-acetonitrile (3-ICN) had little effect on cytochrome P-450 (CYP)-dependent enzyme activities, enzyme induction was observed after in vivo administration of I3C. The treatment of rat liver slices with 50 microM 3,3'-diindolylmethane (DIM; a dimer derived from I3C under acidic conditions) for 72 hours resulted in a marked induction of CYP-dependent enzyme activities. DIM appears to be a mixed inducer of CYP in rat liver slices having effects on CYP1A, CYP2B and CYP3A subfamily isoforms. Small increases in liver slice reduced glutathione levels and glutathione S-transferase activity were also observed after DIM treatment. While aflatoxin B1 and monocrotaline produced a concentration-dependent inhibition of protein synthesis in 72-hour-cultured rat liver slices, cytotoxicity was markedly reduced in liver slices cultured with 50 microM DIM. These results demonstrate that cultured rat liver slices may be employed to evaluate the effects of chemicals derived from cruciferous and other vegetables on CYP isoforms. In addition, liver slices can also be utilized to examine the ability of such chemicals to modulate xenobiotic-induced toxicity.

Aflatoxin B1↗
PubMed2002

Putative role of the orphan nuclear receptor SXR (steroid and xenobiotic receptor) in the mechanism of CYP3A4 inhibition by xenobiotics.

Cytochrome P450 monooxygenase 3A4 (CYP3A4) is responsible for the metabolism of endogenous steroids and drugs in liver. Many inducers of human CYP3A4, such as rifampicin, bind to the orphan nuclear receptor SXR (steroid and xenobiotic receptor) as ligands and stimulate transcription on xenobiotic response elements located in the CYP3A4 promoter. Conversely, it is not known whether SXR mediates the transcriptional repression. We thus examined transcriptional repression of SXR and its interaction with corepressors, NCoR (nuclear receptor corepressor) and SMRT (silencing mediator for retinoid and thyroid receptors) using reporter assays in the absence and presence of ligand. Cotransfection of SMRT, but not NCoR, inhibited not only basal but also rifampicin-induced transcriptional activity of SXR on the CYP3A4 promoter through specific SMRT-SXR interaction in HepG2 cells. Interestingly, rifampicin also increased the interaction of SXR with SMRT as well as with coactivator SRC-1. On the other hand, the anti-fungal agent ketoconazole decreased SXR interaction with both SRC-1 and SMRT. Ketoconazole partially inhibited corticosterone-induced SXR-mediated transcription on the CYP3A4 promoter. Taken together, our results suggest that the differential interaction of coactivators and corepressors induced by various xenobiotics may alter SXR-mediated transcription. Further, the effects of ketoconazole on the CYP3A4 gene suppression may explain, in part, drug-induced inhibition of the CYP3A4 action at the transcriptional level.

Adrenal Cortex Hormones↗
PubMed2004

Highly chlorinated PCBs inhibit the human xenobiotic response mediated by the steroid and xenobiotic receptor (SXR).

Polychlorinated biphenyls (PCBs) are a family of persistent organic contaminants suspected to cause adverse effects in wildlife and humans. In rodents, PCBs bind to the aryl hydrocarbon (AhR) and pregnane X receptors (PXR) inducing the expression of catabolic cytochrome p450 enzymes of the CYP1A and 3A families. We found that certain highly chlorinated PCBs are potent activators of rodent PXR but antagonize its human ortholog, the steroid and xenobiotic receptor (SXR), inhibiting target gene induction. Thus, exposure to PCBs may blunt the human xenobiotic response, inhibiting the detoxification of steroids, bioactive dietary compounds, and xenobiotics normally mediated by SXR. The antagonistic PCBs are among the most stable and abundant in human tissues. These findings have important implications for understanding the biologic effects of PCB exposure and the use of animal models to predict the attendant risk.

Animals↗
PubMed2001

Multiple enhancer units mediate drug induction of CYP2H1 by xenobiotic-sensing orphan nuclear receptor chicken xenobiotic receptor.

Binding of nuclear receptors to drug-responsive enhancer units mediates transcriptional activation of cytochromes P-450 (P-450) by drugs and xenobiotics. In previous studies, a 264-base-pair (bp) phenobarbital-responsive enhancer unit (PBRU) located at -1671 to -1408 upstream of the chicken CYP2H1 transcriptional start-site increased gene expression when activated by the chicken xenobiotic-sensing orphan nuclear receptor CXR. In extension of these studies, we now have functionally analyzed a second distal drug-responsive element and delimited a 643- and a 240-bp PBRU located between 5 and 6 kilobases upstream of the transcriptional start site of CYP2H1. Both PBRUs were activated by CXR after treatment with different drugs. A nuclear receptor binding site, a direct repeat-4 (DR-4) hexamer repeat, was identified on the 240-bp PBRU. Site-directed mutagenesis of this DR-4 abolished activity in reporter gene assays in the chicken hepatoma cells leghorn male hepatoma as well as transactivation of the 240-bp PBRU by CXR in CV-1 cells. CXR bound to this PBRU in electromobility shift assays and the complex remained unaffected by unlabeled 240-bp PBRU with a mutated DR-4. In cross-species experiments, both the human xenobiotic-sensing nuclear receptors pregnane X receptor and constitutive androstane receptor bound to this element, suggesting sequence conservation between chicken and mammalian PBRUs and between the DNA binding domains of these receptors. Of two orphan nuclear receptors involved in cholesterol and bile acid homeostasis, only chicken liver X receptor (LXR) but not chicken farnesoid X receptor bound to the 240-bp PBRU. These results suggest that CYP2H1 induction is explained by the combined effect of multiple distal enhancer elements interacting with multiple transcription factors, including CXR and LXR.

Amino Acid Sequence↗
PubMed2006

Cuticular uptake of xenobiotics into living plants. Part 2: influence of the xenobiotic dose on the uptake of bentazone, epoxiconazole and pyraclostrobin, applied in the presence of various surfactants, into Chenopodium album, Sinapis alba and Triticum aestivum leaves.

This study has determined the uptake of three pesticides, applied as commercial or model formulations in the presence of a wide range of surfactants, into the leaves of three plant species (bentazone into Chenopodium album L. and Sinapis alba L., epoxiconazole and pyraclostrobin into Triticum aestivum L.). The results have confirmed previous findings that the initial dose (nmol mm(-2)) of xenobiotic applied to plant foliage is a strong, positive determinant of uptake. This held true for all the pesticide formulations studied, although surfactant concentration was found to have an effect. The lower surfactant concentrations studied showed an inferior relationship between the amount of xenobiotic applied and uptake. High molecular mass surfactants also produced much lower uptake than expected from the dose uptake equations in specific situations.

Benzothiadiazines↗
PubMed1990

The incorporation of 3-phenoxybenzoic acid and other xenobiotic acids into xenobiotic lipids by enzymes of the monoacylglycerol pathway in microsomes from adult and neonatal tissues.

The incorporation of 3-phenoxybenzoic acid (3PBA) into xenobiotic lipids by enzymes of the monoacylglycerol (MG) pathway was measured using microsomes prepared from rat liver as an enzyme source. The mean activities of the three enzymes involved were: acyl-CoA synthetase, 1.1 nmol/min/mg protein; MG acyltransferase, 75 pmol/min/mg protein; and diacylglycerol acyltransferase, 11.4 pmol/min/mg protein. MG and DG acyltransferase also showed activity with benzoyl-CoA or 1-naphthylacetyl-CoA as acyl donor but none with clofibryl-CoA or 2,4-dichlorophenoxyacetyl-CoA. MG acyltransferase activity, using 3PBA-CoA, was higher in microsomes from rat intestinal mucosa and pig liver, and lower in rat adipose tissue, rat liver and mouse liver. This ranking of activities corresponds to published activities using natural substrates. There was a large increase in MG acyltransferase, using either 3PBA-CoA or palmitoyl-CoA as substrate, in microsomes from the livers of rats 16-18 days old. Lysophosphatidic acid (lyso-PA) and lysophosphatidylethanolamine (lyso-PE), but not other phospholipids or detergents, stimulated MG acyltransferase activity more than two-fold. Lyso-PA (5 microM) increased the Vmax but had little effect on the Km for 2-hexadecylglycerol, whereas 100 microM lyso-PE decreased the Km and had a smaller effect on the Vmax. These results illustrate that the incorporation of xenobiotic acids into diacyl- and triacylglycerol by enzymes of the MG pathway may be a more general phenomenon than was previously suspected and that it may be subject to a variety of developmental and physiological controls.

Acyltransferases↗
PubMed1982

Dietary cholesterol-induced changes of xenobiotic metabolism in liver. I. Influence of xenobiotic administration on hepatic membrane structure.

We have studied the effects of dietary lipids on the structure and function of hepatic endoplasmic reticulum by feeding rats either with a 2% cholesterol or cholesterol-free diet. Rats were further administered either phenobarbitone, carbon tetrachloride, or both in combination to reveal possible differences in the response of the microsomal membranes to xenobiotics. Cholesterol feeding increased the membrane cholesterol contents and also carbon tetrachloride increased microsomal cholesterol contents in those rats fed a cholesterol-free diet. Also the microsomal phospholipid contents were higher in those rats fed 2% cholesterol diet than in those fed cholesterol-free diet and in the 2% cholesterol group also phenobarbitone increased the phospholipid contents. In addition, there were changes in the phospholipid-fatty acid proportions between rats fed 2% cholesterol and cholesterol-free diets. When 1,8-ANS was used as a fluorescence probe, phenobarbitone increased the fluorescence in both the dietary groups, while carbon tetrachloride decreased it; less change was present using PNA as a substrate. When Scatchard plots were constructed phenobarbitone changed the turning point more in the cholesterol-free group than in the 2% cholesterol group, while reversed orders of changes were found with carbon tetrachloride. The results demonstrated that dietary cholesterol has profound effects on the structure of microsomal membranes far beyond changes in their cholesterol content. The membrane fluidity also changes owing to alterations in the phospholipid contents and in their fatty acid composition.

1-Naphthylamine↗
PubMed2000

Molecular and structural aspects of xenobiotic carbonyl metabolizing enzymes. Role of reductases and dehydrogenases in xenobiotic phase I reactions.

The major metabolic pathways involved in synthesis and disposition of carbonyl and hydroxyl group containing compounds are presented, and structural and functional characteristics of the enzyme families involved are discussed. Alcohol and aldehyde dehydrogenases (ADH, ALDH) participate in oxidative pathways, whereas reductive routes are accomplished by members of the aldo-keto reductase (AKR), short-chain dehydrogenases/reductases (SDR) and quinone reductase (QR) superfamilies. A wealth of biochemical, genetic and structural data now establishes these families to constitute important phase I enzymes.

Animals↗