Xenobiotic metabolism

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Blood is red in vertebrates and blue in molluscs thanks to protein–metal complexes. Metalloproteins are involved in all fundamental biochemical processes including respiration, oxygenic photosynthesis, regulation of transcription and translation, nitrogen fixation, and metabolism of xenobiotics. Metalloenzymes were the first biological catalysts on Earth. Later, when the composition of the Earth's atmosphere changed dramatically due to photosynthesis, the metalloproteins evolved to counter the toxic effects of oxygen and harness it for new physiological functions. Currently, over one-half of all proteins are estimated to bind metals. This article introduces but a small number of metalloprotein families, with emphasis on oxidoreductases, electron-transfer proteins, and photosynthetic complexes.

Hydrocarbon spills, waste dumping and gas flaring (gas is separated from oil and, in Nigeria, most of it is burnt as waste) are endemic in the Niger Delta. This pollution, which has affected the area for decades, has damaged the soil, water and air quality. This is a wicked problem. The Niger Delta is one of the 10 most important wetland and coastal marine ecosystems in the world and is home to some 31 million people. The Niger Delta is also the location of massive oil deposits, which have been extracted for decades by the government of Nigeria and by multinational oil companies. Oil has generated an estimated $600 billion since the 1960s.Despite this, the majority of the Niger Delta’s population lives in poverty. The United Nations Development Programme (UNDP) describes the region as suffering from “administrative neglect, crumbling social infrastructure and services, high unemployment, social deprivation, abject poverty, filth and squalor, and endemic conflict.” The majority of the people of the Niger Delta do not have adequate access to clean water or health-care. Their poverty, and its contrast with the wealth generated by oil, has become one of the world’s starkest and most disturbing examples of the “resource curse”. The fact that the people of the Niger Delta have not benefited from oil wealth is only part of the story.
The proposed solution requires human capital training called PC3R Technology®. Tit encapsulate xenobiotic pollution microbial treatment construct techniques for pesticides, herbicides, hydrocarbon, produced water, munitions, heavy metals and others with resultant outcomes for bioremediation, transformation, phytoremediation and mineralization. Remediation bioaugmentation techniques (in situ or ex situ hydrocarbon, RDX, TNT, HMX and heavy metals in soils/water contaminants). Restoration ecology (post in situ or ex situ remediation for zero pollutants impacts of contaminants fate (soils/water) for sustainable re-generative re-use by deploying phytoremediation techniques (phytoextraction, phytotransformation, phytostabilization, phytodegradation and rhizofiltration) in single or combination with potential for accumulating, immobilizing, and transforming contaminants. Reuse, post treatments contaminants soils site for bioenergy crops cultivation converted to biofuel production by application for microbial biofertilizer (bacteria, fungi etcs) to improves crop plant growth, soil ecosystem and biodiversity of the contaminants site.
Keyword:
Hydrocarbon Spill Management, Environmental Remediation Training, Wicked Problem, PC3R Technology, Xenobiotic Pollution, Microbial treatment, Ecosystem restoration and Sustainable development

Kachia 24.95 sq km military training (small arms and artillery weapons) shooting ranges, longitudes 90 55' N and 70 58' E at 732m elevation above sea level, was established 1965 Kaduna, Nigeria. Soil pollutants explosives Xenobiotic four locations was studied where soils samples collected and analysed using EPA SW-846 Method 8095 contains TNT, RDX, HMX and PETN. White rot fungi analysed with amplified using 16srRNA gene of each isolates were processed for sequencing and characterization and contains Lignolytic fungi Aspergillus Niger, Rhizopus spp, Penicillium spp, Trametes versicolor and Phanarochate chrysoporium. Explosives ANOVA test shows significant difference for all locations in both dry and wet seasons (P<0.05) with higher values in dry season with RDX (68.19 mg/kg) highest for both seasons at locations 3 and 4 with artillery weapons. Aspergillus niger had the best ability to degrade explosives while Penicillium spp had the least ability in 1% explosive mineral salt broth supplemented with 1% v/v explosive (P>0.05) from the zero hour to the 5th day and beyond with significant difference in the overall growth pattern. Heavy metal reduction in increasing order were Aspergillus Niger > Phanorochate chrysoporium > Trametes versicolor > Rhizopus spp > Penicillium spp. Xenobiotic biodegradation occurred under co-metabolism with carcinogen potentials to biodiversity.

The human constitutive androstane receptor (CAR, NR1I3) is one of the key regulators of xenobiotic and endobiotic metabolism. The unique properties of human CAR, such as the high constitutive activity and the complexity of signaling, as well as the lack of functional and predictive cell-based assays to study the properties of the receptor, have hindered the discovery of selective human CAR ligands. Here we report a novel human CAR inverse agonist, 1-[(2-methylbenzofuran-3-yl)methyl]-3-(thiophen-2-ylmethyl) urea (S07662), which suppresses human CAR activity, recruits the corepressor NCoR in cell-based assays, and attenuates the phenytoin- and 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO)-induced expression of CYP2B6 mRNA in human primary hepatocytes. The properties of S07662 are also compared with those of known human CAR inverse agonists by using an array of different in vitro and in silico assays. The identified compound S07662 can be used as a chemical tool to study the biological functions of human CAR and also as a starting point for the development of new drugs for various conditions involving the receptor.

Nutritional and environmental epigenetics are involved with the repression of anti-aging genes that are linked to the chronic disease epidemic. Unhealthy diets inactivate the calorie sensitive gene Sirtuin 1 (Sirt 1) involved in epigenetic processes that promote immune system alterations, mitochondrial apoptosis, Non-alcoholic Fatty Liver Disease (NAFLD), diabetes and Nitric Oxide (NO) modification with
relevance to core body temperature involved with appetite regulation, glucose homeostasis and hepatic xenobiotic metabolism. The interplay between NO and epigenetics has attracted interest with relevance to autoimmune disease and mitophagy that has become of critical concern to diabetes and the development of MODS. Future research involved with nutritional research and the maintenance
of Sirt 1 transcriptional control is critical to the prevention of MODS that is linked to the immune system and insulin resistance. In the developing world bacterial lipopolysaccharides a critical repressor of Sirt 1 is now involved with NAFLD and various organ diseases relevant to tissue accumulation of xenobiotics from various environments with relevance to MODS and the global chronic disease epidemic.

Phytoremediation uses living higher plants for the removal and biochemical decomposition of environmental pollutants. In this paper Phase I metabolic pathways in the biotransformation reactions of organic pollutants in plants are reviewed. These reactions result in the introduction of functional groups in the xenobiotic molecule or the exposure of preexisting functional groups and lead to the formation of more polar, more water-soluble, chemically more reactive and sometimes biologically more active derivatives. Phase I type reactions are most important in the phytoremediation of hydrophobic, chemically stable organic pollutants, such as polycyclic aromatic hydrocarbons and (poly)chlorinated aliphatic and aromatic hydrocarbons. Although Phase I reactions involve a wide range of chemical transformations from hydrolysis to reduction, oxidative processes catalyzed by cytochrome P450 containing monooxygenases are the most important. Transgenic plants with tailored Phase I enzymatic activities may play major roles in the removal of environmentally stable organic pollutants from contaminated fields.

The constitutive androstane receptor (CAR; NR1I3) has emerged as one of the main drug- and xenobiotic-sensitive transcriptional regulators. It has a major effect on the expression of several oxidative and conjugative enzymes and transporters, and hence, CAR can contribute to drug/drug interactions. Novel functions for CAR are also emerging: it is able to modulate the metabolic fate of glucose, lipids, and bile acids, and it is also involved in cell-cell communication, regulation of the cell cycle, and chemical carcinogenesis. Here, we will review the recent information available on CAR and its target gene expression, its interactions with partner proteins and mechanisms of action, interindividual and species variation, and current advances in CAR ligand selectivity and methods used in interrogation of its ligands.

Nrf2, a transcriptional activator of cell protection genes, is an attractive therapeutic target for the prevention of neurodegenerative diseases, including Alzheimer's disease (AD). Current Nrf2 activators, however, may exert toxicity and pathway over-activation can induce detrimental effects. An understanding of the mechanisms mediating Nrf2 inhibition in neurode-generative conditions may therefore direct the design of drugs targeted for the prevention of these diseases with minimal side-effects. Our study provides the first in vivo evidence that specific inhibition of Keap1, a negative regulator of Nrf2, can prevent neuronal toxicity in response to the AD-initiating Aβ42 peptide, in correlation with Nrf2 activation. Comparatively , lithium, an inhibitor of the Nrf2 suppressor GSK-3, prevented Aβ42 toxicity by mechanisms independent of Nrf2. A new direct inhibitor of the Keap1-Nrf2 binding domain also prevented synaptotoxicity mediated by naturally-derived Aβ oligomers in mouse cortical neurons. Overall, our findings highlight Keap1 specifically as an efficient target for the re-activation of Nrf2 in AD, and support the further investigation of direct Keap1 inhibitors for the prevention of neurodegeneration in vivo.

To test the hypothesis that hepatic regulation of α-tocopherol metabolism would be sufficient to prevent over-accumulation of α-tocopherol in extrahepatic tissues and that administration of high doses of α-tocopherol would up-regulate extrahepatic xenobiotic pathways, rats received daily subcutaneous injections of either vehicle or 0.5, 1, 2, or 10 mg α-tocopherol/100 g body wt for 9 days. Liver α-tocopherol increased 15-fold in rats given 10 mg α-tocopherol/100 g body weight (mg/100 g) compared with controls. Hepatic α-tocopherol metabolites increased with increasing α-tocopherol doses, reaching 40-fold in rats given the highest dose. In rats injected with 10 mg/100 g, lung and duodenum α-tocopherol concentrations increased 3-fold, while α-tocopherol concentrations of other extrahepatic tissues increased 2-fold or less. With the exception of muscle, daily administration of less than 2 mg/100 g) failed to increase α-tocopherol concentrations in extrahepatic tissues. Lung cytochrome P450 3A and 1A levels were unchanged by administration of α-tocopherol at any dose. In contrast, lung P-glycoprotein (MDR-1) levels increased dose dependently and expression of this xenobiotic transport protein was correlated with lung α-tocopherol concentrations (R2 = 0.88, P < 0.05). Increased lung MDR1 may provide protection from exposure to environmental toxins by increasing alveolar space α-tocopherol.

Benzo[a]pyrene (BaP) is bioactivated in most organisms by the cytochrome P450 (CYP) enzymes, mainly CYP1A1, ultimately resulting in the reactive metabolite BaP-7,8-dihydrodiol-9,10-epoxide (BPDE) capable of covalently binding to DNA and forming adducts. This step has been defined as the key process in cancer initiation in humans. However, limited knowledge is available about the consequences of BaP exposure in organisms lacking this classical CYP1A1 pathway, one example is the model nematode Caenorhabditis elegans. The aim of this study was to define the genotoxic potential of BaP in C. elegans and to advance our understanding of xenobiotic processing in the absence of the CYP1A1 pathway. Exposure to high concentrations of BaP (0-40 µM) significantly affected life cycle endpoints of C. elegans, which were manifested by a reduced reproductive output and shortened life span. An optimised comet assay revealed that DNA damage increased in a dose-dependent manner; however, no bulky DNA adducts (dG-N 2-BPDE) were observed by 32 P-postlabelling. Global transcriptomic analysis by RNA-Seq identified responsive transcript families, most prominently members of the cyp-35 and UDP-glucuronosyltransferases (UGTs) enzyme families, both of which are linked to xenobiotic metabolism. Strains harbouring mutations in the cyp-35A2 and cyp-35A3 genes were notably less prone to BaP-mediated toxicity, and BaP led to longevity in cyp-35A5 mutants. In summary, BaP induces transcriptional, genotoxic and phenotypic responses in C. elegans, despite the absence of the classical CYP1A1 bioactivation pathway. This provides first evidence that parallel pathways are implicated in BaP metabolism in C. elegans and this seems to be mediated via the cyp-35 pathway.

Carbonyl reduction to the respective alcohol metabolites of the anti-insect agent imidazole analogue of metyrapone, NKI 42255 (2-(1-imidazolyl)-1-(4-methoxyphenyl)-2-methyl-1-propanone) and its parent compound metyrapone was characterized in subcellular fractions from soil bacteria, as well as insect, invertebrate and teleost species. The enzymes involved in this metabolic step were characterized with respect to their cosubstrate specificities, inhibitor susceptibilities, and immunological crossreactivities with antibodies directed against previously described bacterial and mammalian hydroxysteroid dehydrogenases/carbonyl reductases (HSD/CR). All fractions investigated rapidly reduced metyrapone, with highest specific activities found in insect, invertebrate and vertebrate fractions. Except for the insect fractions, all species examined reduced the NKI compound. Cosubstrate dependence and inhibitor specificities suggest that the enzymes described belong to the protein superfamilies of short-chain dehydrogenases/reductases (SDR) or aldo-keto reductases (AKR). Immunological crossreactions to the previously established subgroup of HSD/CRs were found in trout liver microsomes and insect homogenates, but not in all bacterial extracts or earthworm microsomes. These findings suggest that the high CR activities found in these fractions belong to different subgroups of SDR or AKR.