Metabolism of organochlorine pesticides: The role of human cytochrome P450 3A4

Mehmood, Zahid; Williamson, Michael P.; Kelly, Diane; Kelly, Steven L.

doi:10.1016/0045-6535(96)00212-3

Cited by 33 publications

(18 citation statements)

References 19 publications

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“…Previous studies indicate that principal mechanisms of action of PCP-induced toxicity seem to be related to the uncoupling of oxidative phosphorylation in mitochondria and the generation of reactive oxygen species (ROS) [17,29]. PCP undergoes oxidative dechlorination to form tetrachlorohydroquinone (TCHQ) by cytochrome P450 enzymes, resulting in oxidative stress on cells and tissues [30,31]. TCHQ seems to be a more toxic metabolic product of PCP; it can induce DNA strand breakage and deplete glutathione content [32,33].…”

Section: Introductionmentioning

confidence: 99%

Effect of titanium dioxide nanoparticles on the bioavailability, metabolism, and toxicity of pentachlorophenol in zebrafish larvae

Fang

Shi

Zhang

et al. 2015

Journal of Hazardous Materials

134

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Section: Introductionmentioning

confidence: 99%

Effect of titanium dioxide nanoparticles on the bioavailability, metabolism, and toxicity of pentachlorophenol in zebrafish larvae

Fang

Shi

Zhang

et al. 2015

Journal of Hazardous Materials

134

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“…Hexachlorobenzene is biotransformed by cytochrome P450 isoenzymes of rat liver microsomes to pentachlorobenzene, pentachlorophenol, tetrachloro-1,2-benzenediol, tetrachloro-1,4-benzenediol and the very reactive metabolite tetrachloro-1,4-benzoquinone (Stewart and Smith, 1986;Van Ommen and Van Bladeren, 1989). The same biotransformation pathway has been observed in cells of S. cerevisiae expressing human cytochrome P450 3A4 (Mehmood et al, 1996). In addition to hydroxylation reactions, evidence has been obtained for conjugation of hexachlorobenzene with glutathione and the presence in rat urine of N-acetyl-S-(pentachlorophenyl) cysteine (Den Besten et al, 1994).…”

Section: Hexachlorobenzenementioning

confidence: 56%

Failure of the standard battery of short-term tests in detecting some rodent and human genotoxic carcinogens

Brambilla

Martelli

2004

Toxicology

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“…[27] In this pathway, pentachlorophenol is dehalogenated oxidatively to tetrachlorohydroquinone. [27b, d, 28] This metabolic process has recently been shown to be CYP-mediated in the white rot fungus, Phanerochaete chrysosporium ,[28a] by human cytochrome P450 3A4,[28b and CYP involvement is also suspected in Mucor ramosissimus [29] and Mycobacterium chlorophenolicum. [30]…”

Section: Resultsmentioning

confidence: 99%

Biofragments: An Approach towards Predicting Protein Function Using Biologically Related Fragments and its Application to Mycobacterium tuberculosis CYP126

et al. 2014

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We present a novel fragment-based approach that tackles some of the challenges for chemical biology of predicting protein function. The general approach, which we have termed biofragments, comprises two key stages. First, a biologically relevant fragment library (biofragment library) can be designed and constructed from known sets of substrate-like ligands for a protein class of interest. Second, the library can be screened for binding to a novel putative ligand-binding protein from the same or similar class, and the characterization of hits provides insight into the basis of ligand recognition, selectivity, and function at the substrate level. As a proof-of-concept, we applied the biofragments approach to the functionally uncharacterized Mycobacterium tuberculosis (Mtb) cytochrome P450 isoform, CYP126. This led to the development of a tailored CYP biofragment library with notable 3D characteristics and a significantly higher screening hit rate (14 %) than standard drug-like fragment libraries screened previously against Mtb CYP121 and 125 (4 % and 1 %, respectively). Biofragment hits were identified that make both substrate-like type-I and inhibitor-like type-II interactions with CYP126. A chemical-fingerprint-based substrate model was built from the hits and used to search a virtual TB metabolome, which led to the discovery that CYP126 has a strong preference for the recognition of aromatics and substrate-like type-I binding of chlorophenol moieties within the active site near the heme. Future catalytic analyses will be focused on assessing CYP126 for potential substrate oxidative dehalogenation.

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Metabolism of organochlorine pesticides: The role of human cytochrome P450 3A4

Cited by 33 publications

References 19 publications

Effect of titanium dioxide nanoparticles on the bioavailability, metabolism, and toxicity of pentachlorophenol in zebrafish larvae

Effect of titanium dioxide nanoparticles on the bioavailability, metabolism, and toxicity of pentachlorophenol in zebrafish larvae

Failure of the standard battery of short-term tests in detecting some rodent and human genotoxic carcinogens

Biofragments: An Approach towards Predicting Protein Function Using Biologically Related Fragments and its Application to Mycobacterium tuberculosis CYP126

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