P450 in the rat and man: methods of investigation, substrate specificities and relevance to cancer

Nedelcheva, Vessela; Gut, Ivan

doi:10.3109/00498259409038673

Cited by 135 publications

(80 citation statements)

References 87 publications

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“…A significant correlation was reported between enzyme activity and mRNA expression for CYP3A4 in human liver samples (30). Rat CYP3A2 and human CYP3A4 are involved in the metabolism of erythromycin, nifedipine, lidocaine, testosterone, aflatoxin B1 and benzo[a]pyrene (28,30). Furthermore, CYP3A4 is highly expressed in the adult liver and small intestine (30), and metabolizes xenobiotics and carcinogens (32,33), as well as numerous endogenous compounds, such as bile acids, cholesterol, prostaglandins, fatty acids, retinoids, leukotrienes and biogenic amines (32,34).…”

Section: Discussionmentioning

confidence: 98%

“…The induction of CYP3A2 by carbonated SDs may indicate its potential ability to induce human CYP3A4 due to their close homology (29). A significant correlation was reported between enzyme activity and mRNA expression for CYP3A4 in human liver samples (30). Rat CYP3A2 and human CYP3A4 are involved in the metabolism of erythromycin, nifedipine, lidocaine, testosterone, aflatoxin B1 and benzo[a]pyrene (28,30).…”

Section: Discussionmentioning

confidence: 99%

“…Rat CYP3A2 and human CYP3A4 are involved in the metabolism of erythromycin, nifedipine, lidocaine, testosterone, aflatoxin B1 and benzo[a]pyrene (28,30). Furthermore, CYP3A4 is highly expressed in the adult liver and small intestine (30), and metabolizes xenobiotics and carcinogens (32,33), as well as numerous endogenous compounds, such as bile acids, cholesterol, prostaglandins, fatty acids, retinoids, leukotrienes and biogenic amines (32,34). The induction of CYP3A2 by SDC may be attributed to the presence of taurine, as it was demonstrated that taurine enhanced the induction of CYP3A4 by rifampicin in HepG2 cells (35).…”

Section: Discussionmentioning

confidence: 99%

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Carbonated soft drinks alter hepatic cytochrome P450 isoform expression in Wistar rats

2016

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Abstract.The aim of the current study was to examine the effects of chronic consumption of soft drinks (SDs) on hepatic oxidative stress and cytochrome P450 enzymes (CYPs) expression in the livers of Wistar rats. For 3 consecutive months, the rats had free access to three different soft drinks, Coca-Cola, Pepsi-Cola and 7-UP. The rats were subsequently compared with control group rats that had consumed water. Blood and hepatic tissue samples were assayed for the changes in antioxidants, liver function biomarkers and hepatic gene expression for different isoforms of hepatic CYP. The results indicated that SD consumption (SDC) decreased serum antioxidant levels and increased malondialdehyde secretion, and increased liver biomarkers (glutamate pyruvate transaminase and glutamate oxaloacetate). SD induced alterations in mRNA expression of hepatic antioxidants and cytochrome isoforms. The expression of peroxidase, catalase, CYP1A2, CYP3A2 and CYP2C11 in the liver were upregulated following SDC. By contrast, CYP2B1 was downregulated after 3 months of SDC in liver tissue samples. Thus, the present findings indicate that SDs induced oxidative stress in the liver of Wistar rats and for the first time, to the best of our knowledge, indicate that SDC disrupts hepatic CYP enzymes that may affect drug metabolism. Therefore, drug-dosing programs should be carefully designed to take these novel findings into consideration for the treatment of diseases.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Carbonated soft drinks alter hepatic cytochrome P450 isoform expression in Wistar rats

2016

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“…25-30% of the original activity remaining. In retrospect, we now know that as substrates, aminopyrine and p-nitroanisole are relatively non-selective among common P450 isoforms [43]. Thus there could be several possible explanations for the observed incompleteness of the inactivation process.…”

Section: Discussionmentioning

confidence: 99%

Cyclopropylamine inactivation of cytochromes P450: Role of metabolic intermediate complexes

Cerny

Hanzlik

2005

Archives of Biochemistry and Biophysics

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, "Cyclopropylamine inactivation of cytochromes P450. Role of metabolic intermediate complexes." Arch. Biochem. Biophys. 436, 265-275 (2005). Keywords:Cytochrome P450, flavin-containing monooxygenase, metabolic intermediate complex, mechanismbased inactivation, suicide substrate Abstract:The inactivation of cytochrome P450 enzymes by cyclopropylamines has been attributed to a mechanism involving initial one-electron oxidation at nitrogen followed by scission of the cyclopropane ring leading to covalent modification of the enzyme. Herein we report that in liver microsomes Ncyclopropylbenzylamine (1) and related compounds inactivate P450 to a large extent via formation of metabolic intermediate complexes (MICs) in which a nitroso metabolite coordinates tightly to the heme iron, thereby preventing turnover. MIC formation from 1 does not occur in reconstituted P450 systems with CYP2B1/2, 2C11 or 2E1, or in microsomes exposed to gentle heating to inactivate the flavincontaining monooxygenase (FMO). In contrast, N-hydroxy-N-cyclopropylbenzylamine (3) and Nbenzylhydroxylamine (4) generate MICs much faster than 1 in both reconstituted and microsomal systems. MIC formation from nitrone 5 (PhCH=N(O)cPr) is somewhat faster than from 1, but very much faster than the hydrolysis of 5 to a primary hydroxylamine. Thus the major overall route from 1 to a P450 MIC complex would appear to involve FMO oxidation to 3, further oxidation by P450 and/or FMO to nitrone 5' (C2H4C=N(O)CH2Ph), hydrolysis to 4, and P450 oxidation to α-nitrosotoluene as the precursor to oxime 2 and the major MIC from 1.

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“…Another limitation of this early work is the use of rat liver microsomes (RLMs) as the enzyme source. Considerable differences exist between the expression and substrate selectivities of human and rat CYP [Nedelcheva and Gut, 1994], so caution is necessary when extrapolating such findings to humans. In particular, a role for the CYP2C subfamily could not be investigated because female rats were used and selective inhibitors and inducers of CYP2C enzymes were not available at the time [Savi et al 1994].…”

Section: Studies By Sanofimentioning

confidence: 99%

Metabolic activation of clopidogrel: in vitro data provide conflicting evidence for the contributions of CYP2C19 and PON1

Polasek

Doogue

Miners

2011

Therapeutic Advances in Drug Safety

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The recent report that clopidogrel efficacy may be more dependent on paraoxonase-1 (PON1) than on cytochrome P450 2C19 (CYP2C19) activity raises questions about the roles of these and other enzymes in clopidogrel activation. To provide insight into the emerging PON1 versus CYP2C19 debate, this commentary summarizes the clinical evidence on the pharmacokinetic determinants of clopidogrel efficacy. We then review the in vitro studies investigating the enzymes involved in clopidogrel activation, and comment on their strengths and limitations. There is agreement amongst in vitro studies regarding the involvement of CYP1A2 and CYP2B6 in the metabolism of clopidogrel to 2-oxo-clopidogrel. However, the evidence for other CYP enzymes in the first activation step (e.g. CYP2C19 and CYP3A4) is inconsistent and dependent on the in vitro test system and laboratory. All major drug metabolizing CYP enzymes are capable of converting 2-oxo-clopidogrel to sulfenic acid intermediates that subsequently form the active thiol metabolite. However, the extent of CYP involvement in this second step has been challenged, and new evidence suggests that CYP-independent hydrolytic cleavage of the thioester bond may be more important than oxidative metabolism.

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P450 in the rat and man: methods of investigation, substrate specificities and relevance to cancer

Cited by 135 publications

References 87 publications

Carbonated soft drinks alter hepatic cytochrome P450 isoform expression in Wistar rats

Carbonated soft drinks alter hepatic cytochrome P450 isoform expression in Wistar rats

Cyclopropylamine inactivation of cytochromes P450: Role of metabolic intermediate complexes

Metabolic activation of clopidogrel: in vitro data provide conflicting evidence for the contributions of CYP2C19 and PON1

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