Cytochrome P450 3A4 mediated metabolism of 2,4-dichlorophenol

Mehmood, Zahid; Kelly, Diane; Kelly, Steven L.

doi:10.1016/s0045-6535(97)00040-4

Cited by 25 publications

(14 citation statements)

References 19 publications

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“…This is possible because 2,4‐DCP does not accumulate in body tissues and is quickly metabolized or excreted in the urine as conjugated metabolites [35]. It has been shown in studies using microsomes that 2,4‐DCP is metabolized via cytochrome P‐450 isozymes to two major metabolites, 2‐chloro‐1,4‐hydroxyquinone and 2‐chloro‐1,4‐benzoquinone [36].…”

Section: Discussionmentioning

confidence: 99%

Electron paramagnetic resonance investigation of in vivo free radical formation and oxidative stress induced by 2,4‐dichlorophenol in the freshwater fishCarassius auratus

Luo

Wang

Shi

et al. 2005

Enviro Toxic and Chemistry

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In the present study, electron paramagnetic resonance coupled with spin-trapping technique was used, with alpha-phenyl-N-tert-butylnitrone (PBN) as a spin-trapping agent, to investigate free radical generation in freshwater fish with acute 2,4-dichlorophenol (2,4-DCP) poisoning. The PBN-radical adducts were detected in fish liver samples following treatments of 2,4-DCP (0.025, 0.05, 0.5, 5, or 25 mg/kg) 24 h after intraperitoneal (i.p.) injection and 2,4-DCP (0.5 mg/kg) at 2, 4, 8, 24, or 72 h after i.p. injection in Carassius auratus. The hyperfine splitting constants for the PBN-radical adducts are aN = 13.7 G, aH = 1.8 G, and g = 2.0058, which is consistent with those of PBN/hydroxyl radical (*OH). The results indicate that the hydroxyl radical is probably produced during acute intoxication of 2,4-DCP. The relative similarity in the kinetics (from 2 to 72 h) of superoxide dismutase activity induction and *OH generation implies that the generation of *OH possibly depends on the superoxide anion (O2*-). Superoxide anion (O2*-) might be the precursor radical undergoing the Haber-Weiss reaction to form *OH. Possible pathways for radical chain reactions in the formation of the hydroxyl radical in vivo after 2,4-DCP administration are proposed. Other parameters with respect to antioxidant defense (e.g., superoxide dismutase and catalase) and oxidative damage (lipid peroxidation level) indicate that the fish were subjected to oxidative stress induced by 2,4-DCP and that the mechanisms of oxidative stress possibly involve the in vivo stimulation of hydroxyl radical formation.

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Section: Discussionmentioning

confidence: 99%

Electron paramagnetic resonance investigation of in vivo free radical formation and oxidative stress induced by 2,4‐dichlorophenol in the freshwater fishCarassius auratus

Luo

Wang

Shi

et al. 2005

Enviro Toxic and Chemistry

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“…We found that the inhibition of ER stress impaired protein expression of Bip and 2,4‐DCP‐induced apoptosis, which verified that ER stress mediated 2,4‐DCP‐induced apoptosis. These results could be explained by that 2,4‐DCP served as a substituted phenol, might cause ER stress‐mediated apoptosis directly like nonylphenol, and/or indirectly by its metabolites such as hydroquinone and/or benzoquinone (Mehmood et al, ; Dai et al, ).…”

Section: Discussionmentioning

confidence: 99%

2,4‐dichlorophenol induces ER stress‐mediated apoptosis via eIF2α dephosphorylation in vitro

Zhang

et al. 2014

Environmental Toxicology

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2,4-Dichlorophenol (2,4-DCP) has been widely used to produce herbicides and pharmaceutical intermediates, which exhibits various toxic effects including apoptosis. However, the mechanisms underlying 2,4-DCP-induced apoptosis, especially mediated by endoplasmic reticulum (ER) stress, are still unknown. In the present study, the mouse embryonic fibroblasts (MEFs) were used as an in vitro model system to figure out whether 2,4-DCP could induce ER stress, and further to elucidate the role of ER stress in 2,4-DCP-induced apoptosis. The results showed that 2,4-DCP dramatically caused the decrease of cell viability, the increase of apoptotic cells, the collapse of mitochondrial membrane potential (MMP) and the activation of caspase-3, suggesting that 2,4-DCP did induce apoptosis. Meanwhile, 2,4-DCP acted similarly as ER stress agonist tunicamycin (Tu) to activate all three branches (IRE1α, ATF6 and eIF2α) of ER stress. Furthermore, repression of ER stress or inhibition of eIF2α dephosphorylation significantly alleviated 2,4-DCP-induced apoptosis. Taking these results together, the present study firstly showed that 2,4-DCP induced ER stress-mediated apoptosis via eIF2α dephosphorylation in mammalian cells. These findings will provide new insights into the mechanisms underlying apoptosis after chlorophenols exposure.

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“…cerevisiae AH22 is considered a standard host for mammalian cyp gene expression [35,55,57], whereas BY4741 is, in general, frequently used as a host for biotechnological and biochemical studies [44]. Both strains have a leucine auxotrophic phenotype, which was used to select for plasmid-containing strains.…”

Section: Catalytic Activity Of Rat Cyp1a1 In S Cerevisiaementioning

confidence: 99%

Comparison of microbial hosts and expression systems for mammalian CYP1A1 catalysis

Cornelissen

Julsing

Schmid

et al. 2012

Journal of Industrial Microbiology and Biotechnology

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Mammalian cytochrome P450 enzymes are of special interest as biocatalysts for fine chemical and drug metabolite synthesis. In this study, the potential of different recombinant microorganisms expressing rat and human cyp1a1 genes is evaluated for such applications. The maximum specific activity for 7-ethoxyresorufin O-deethylation and gene expression levels were used as parameters to judge biocatalyst performance. Under comparable conditions, E. coli is shown to be superior over the use of S. cerevisiae and P. putida as hosts for biocatalysis. Of all tested E. coli strains, E. coli DH5α and E. coli JM101 harboring rat CYP1A1 showed the highest activities (0.43 and 0.42 U g⁻¹(CDW), respectively). Detection of active CYP1A1 in cell-free E. coli extracts was found to be difficult and only for E. coli DH5α, expression levels could be determined (41 nmol g⁻¹(CDW)). The presented results show that efficient expression of mammalian cyp1a1 genes in recombinant microorganisms is troublesome and host-dependent and that enhancing expression levels is crucial in order to obtain more efficient biocatalysts. Specific activities currently obtained are not sufficient yet for fine chemical production, but are sufficient for preparative-scale drug metabolite synthesis.

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Cytochrome P450 3A4 mediated metabolism of 2,4-dichlorophenol

Cited by 25 publications

References 19 publications

Electron paramagnetic resonance investigation of in vivo free radical formation and oxidative stress induced by 2,4‐dichlorophenol in the freshwater fishCarassius auratus

Electron paramagnetic resonance investigation of in vivo free radical formation and oxidative stress induced by 2,4‐dichlorophenol in the freshwater fishCarassius auratus

2,4‐dichlorophenol induces ER stress‐mediated apoptosis via eIF2α dephosphorylation in vitro

Comparison of microbial hosts and expression systems for mammalian CYP1A1 catalysis

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