Cytochrome P450 2E1 is the primary enzyme responsible for low-dose carbon tetrachloride metabolism in human liver microsomes

Zangar, Richard C.; Benson, Janet M.; Burnett, Vicki L.; Springer, David L.

doi:10.1016/s0009-2797(00)00149-6

Cited by 98 publications

(58 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Regarding reductive metabolism, in the rat constitutive isoforms and CYP2B1/2 at high CHCl 3 concentrations were identified as active, and no contribution has been attributed to CYP2E1 . A similar situation was reported for CCl 4 : CYP2B has been implicated in its reductive metabolism in rodent (Frank et al, 1982), whereas in HLM the only isoform active in the reaction was CYP2E1 (Zangar et al, 2000).…”

Section: Discussionsupporting

confidence: 75%

“…However, considering results from the multifaceted approach with HLM, the reductive process appeared to be mediated by a single P450, identified as CYP2E1: Ch6OH strongly correlated with PL-RAD formation, which was decreased only by 4MPYR and anti-CYP2E1 Ab. In line with this result, CYP2E1 has been indicated as the primary isoform responsible for CCl 4 reduction in the human liver (Zangar et al, 2000). On the contrary, although the quite similar chemical structure, halothane reductive metabolism has been reported to be catalyzed by two different P450s, namely 2A6 and 3A4 (Spracklin et al, 1996).…”

Section: Discussionmentioning

confidence: 90%

See 1 more Smart Citation

Metabolism of Chloroform in the Human Liver and Identification of the Competent P450s

Gemma¹,

Vittozzi²,

Testai³

2003

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:The oxidative and reductive cytochrome P450 (P450)-mediated chloroform bioactivation has been investigated in human liver microsomes (HLM), and the role of human P450s have been defined by integrating results from several experimental approaches: cDNA-expressed P450s, selective chemical inhibitors and specific antibodies, correlation studies in a panel of phenotyped HLM. HLM bioactivated CHCl 3 both oxidatively and reductively. Oxidative reaction was characterized by two components, suggesting multiple P450 involvement. The high affinity process was catalyzed by CYP2E1, as clearly indicated by kinetic studies, correlation with chlorzoxazone 6-hydroxylation (r ‫؍‬ 0.837; p < 0.001), and inhibition by monoclonal antihuman CYP2E1 and 4-methylpyrazole. The low affinity phase of oxidative metabolism was essentially catalyzed by CYP2A6. This conclusion was supported by the correlation with coumarin 7-hydroxylase (r ‫؍‬ 0.777; p < 0.01), inhibition by coumarin and by the specific antibody, in addition to results with heterologously expressed P450s. Chloroform oxidation was poorly dependent on pO 2 , whereas the reductive metabolism was highly inhibited by O 2 . The production of dichloromethyl radical was significant only at CHCl 3 concentration >1 mM, increasing linearly with substrate concentration. CYP2E1 was the primary enzyme involved in the reductive reaction, as univocally indicated by all the different approaches. The reductive pathway seems to be scarcely relevant in the human liver, since it is active only at high substrate concentrations, and in strictly anaerobic conditions. The role of human CYP2E1 in CHCl 3 metabolism at low levels, typical of actual human exposure, provides insight into the molecular basis for eventual difference in susceptibility to chloroform-induced effects due to either genetic, pathophysiological, or environmental factors.

show abstract

Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 90%

Metabolism of Chloroform in the Human Liver and Identification of the Competent P450s

Gemma¹,

Vittozzi²,

Testai³

2003

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…CCl 4 exposure can damage the liver due to cytochrome p450-dependent reduction of CCl 4 to the reactive trichloromethyl radical (Zangar et al, 2000), which in turn leads to CCl 4 hepatotoxicity by initiating lipid peroxidation in the cell membranes (Bahcecioglu et al, 1999). Many published studies demonstrate that oxidative damage can be limited by naturally occurring substances in plants.…”

Section: Discussionmentioning

confidence: 99%

Hepatoprotection of emodin andPolygonum multiflorumagainst CCl₄-induced liver injury

Lee

Huang

Duh

et al. 2011

Pharmaceutical Biology

View full text Add to dashboard Cite

“…In contrast, the administration of CYP3A inhibitors decreased LPS-stimulated production of NO and prevented hepatic damage. 28) Furthermore, it has been observed that toxicity of carbon tetrachloride (CCl 4 ) depended on CYP2E1 mediated formation of ROS and toxic metabolites, 30) in consequence causing membrane lipid peroxidation, mitochondrial DNA oxidative damage and cell apoptosis. 31) CYP1A2 is another phase I metabolic enzyme specifically expressed in the liver.…”

Section: Effects Of Glps On P450 Total Contents In Bcginduced Hepaticmentioning

confidence: 99%

Effects of Ganoderma lucidum Polysaccharide on CYP2E1, CYP1A2 and CYP3A Activities in BCG-Immune Hepatic Injury in Rats

Wang

Zhao

et al. 2007

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Ganoderma lucidum (LEYSS, ex FR., G. lucidum) KARST has been prescribed to improve health and longevity in the traditional Chinese medicine, and it was used for the treatment of neurasthenia, hypertension, hepatopathy and carcinoma for thousands of years.1) More than one hundred species of bioactive components have been isolated from G. lucidum,2) such as polysaccharides, triterpenoids and alkaloids, in which that Ganoderma lucidum polysaccharide (GLPS) is one of the major active components. Its multiple pharmacological effects, such as antitumor, 3) antioxidation, 4) immunomodulation 5,6) and especially hepatoprotection against chemical or immune hepatic damage, 4,7) have been demonstrated in many animal models in vivo and in vitro. However, the accurate protective mechanism of GLPS on the liver damage is still unknown.Cytochrome P450 (P450) monooxygenase superfamily is the most important phase I metabolic enzyme system in liver. P450 is not only responsible for the oxidative metabolism of numerous exogenous compounds and endogenous hormones, but also plays a critical role involving in the activation of various chemical toxicant and procarcinogen. 8) There are researches which have confirmed that the expressions and activities of some P450 isoenzymes may be down-regulated under the inflammatory or infecting condition, and then resulting in change of the metabolic capability of the enzymes.9) However, whether P450 down-regulation is a homeostatic mechanism or a pathophysiological phenomenon has not been elucidated. On the other hand, because G. lucidum is currently popularly used as self-medication in East Asia, 1) thus, it is needed to be investigated that whether GLPS influences P450 metabolic activity.Bacillus Calmette Guérin (BCG), a live attenuated Mycobacterium bovis, is clinically used as a preventing vaccine for tuberculosis or therapeutic regimens for bladder cancer.10) On the other hand, some cases of disseminated BCG infection have been proven to induce granulomatous hepatitis, sepsis and multiple organ failure in these patients.11) Several animal experiments have confirmed that BCG infection could induce the immune hepatic injury and production of inflammatory cytokines, active free radicals and nitric oxide (NO). 12) Moreover, it was reported that microsomal P450 content and activity were suppressed by NO from inducible nitric oxide synthase (iNOS) during BCG infection in rodent liver.13) Therefore, the pharmacokinetics of P450 metabolized substrates may be changed by BCG in clinical patients, leading to enhancement of the therapeutic or adverse effects of drugs.In our previous experiment, it has been observed that GLPS inhibits iNOS expression or NO production, and mitigates immune liver injury induced by BCG in mice in vivo and in vitro.7) The purpose of the present study was to investigate the effect of GLPS on the metabolic activities of three P450 isoenzymes including CYP2E1, CYP1A2 and CYP3A, which are abundantly expressed in liver, and further to evaluate whether GLPS modulating P450 activity...

show abstract

Cytochrome P450 2E1 is the primary enzyme responsible for low-dose carbon tetrachloride metabolism in human liver microsomes

Cited by 98 publications

References 17 publications

Metabolism of Chloroform in the Human Liver and Identification of the Competent P450s

Metabolism of Chloroform in the Human Liver and Identification of the Competent P450s

Hepatoprotection of emodin andPolygonum multiflorumagainst CCl₄-induced liver injury

Effects of Ganoderma lucidum Polysaccharide on CYP2E1, CYP1A2 and CYP3A Activities in BCG-Immune Hepatic Injury in Rats

Contact Info

Product

Resources

About

Cytochrome P450 2E1 is the primary enzyme responsible for low-dose carbon tetrachloride metabolism in human liver microsomes

Cited by 98 publications

References 17 publications

Metabolism of Chloroform in the Human Liver and Identification of the Competent P450s

Metabolism of Chloroform in the Human Liver and Identification of the Competent P450s

Hepatoprotection of emodin andPolygonum multiflorumagainst CCl4-induced liver injury

Effects of Ganoderma lucidum Polysaccharide on CYP2E1, CYP1A2 and CYP3A Activities in BCG-Immune Hepatic Injury in Rats

Contact Info

Product

Resources

About

Hepatoprotection of emodin andPolygonum multiflorumagainst CCl₄-induced liver injury