Stimulation of Cytochrome P450 Reactions by Apo-cytochromeb 5

Yamazaki, Hiroshi; Shimada, Tsutomu; Martin, Martha V.; Guengerich, F. Peter

doi:10.1074/jbc.m105011200

Cited by 95 publications

(31 citation statements)

References 64 publications

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“…42,68,77−82 Furthermore, several studies have demonstrated that addition of apo (heme free) b5 can stimulate the activities of many CYPs, including CYP3A4, CYP2C9, and CYP17. 7,83−85 It has been postulated that, in certain cases at least, b5 exerts the majority of its effects in the absence of electron transfer. 77,86−89 It is still not completely clear if b5 functions solely as an electron donor, allosteric modulator, electron sink, or an uncoupling inhibitor.…”

Section: Cytochrome P450 Interactions With Cytochrome P450 Reductase mentioning

confidence: 99%

Role of Protein–Protein Interactions in Cytochrome P450-Mediated Drug Metabolism and Toxicity

Kandel

Lampe

2014

Chem. Res. Toxicol.

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Through their unique oxidative chemistry, cytochrome P450 monooxygenases (CYPs) catalyze the elimination of most drugs and toxins from the human body. Protein–protein interactions play a critical role in this process. Historically, the study of CYP–protein interactions has focused on their electron transfer partners and allosteric mediators, cytochrome P450 reductase and cytochrome b5. However, CYPs can bind other proteins that also affect CYP function. Some examples include the progesterone receptor membrane component 1, damage resistance protein 1, human and bovine serum albumin, and intestinal fatty acid binding protein, in addition to other CYP isoforms. Furthermore, disruption of these interactions can lead to altered paths of metabolism and the production of toxic metabolites. In this review, we summarize the available evidence for CYP protein–protein interactions from the literature and offer a discussion of the potential impact of future studies aimed at characterizing noncanonical protein–protein interactions with CYP enzymes.

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Section: Cytochrome P450 Interactions With Cytochrome P450 Reductase mentioning

confidence: 99%

Role of Protein–Protein Interactions in Cytochrome P450-Mediated Drug Metabolism and Toxicity

Kandel

Lampe

2014

Chem. Res. Toxicol.

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“…Third, serine/threonine phosphorylation of P450c17 increases 17,20 lyase activity but does not affect 17␣-hydroxylase activity (28,29). In some P450-mediated drug metabolism reactions, cytochrome b 5 appears to act as an alternative electron donor that can substitute for POR in the donation of second electron in the P450 cycle (30 -32) but it does not function in this fashion to foster 17,20 lyase activity, as apo b 5 , which is devoid of heme, is as effective as holo b 5 (13,32). Mutations in the POR binding site of P450c17 selectively reduce 17,20 lyase activity (33); when cytochrome b 5 is added, 17,20 lyase activity is partially restored, increasing the V max but not influencing the K m of the mutants (27), thus confirming the allosteric action of cytochrome b 5 .…”

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confidence: 99%

Regulation of 17,20 Lyase Activity by Cytochrome b5 and by Serine Phosphorylation of P450c17

Pandey

Miller

2005

Journal of Biological Chemistry

144

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“…The mode of action of cytochrome b 5 remains controversial (Kumar et al ., 2005). Although the role of this protein as a source of electrons for CYPs is well known (Guryev et al ., 2001, Schenkman and Jansson 1999, Yamazaki et al ., 2001), increasing evidence points to an allosteric effects of cytochrome b 5 mediated in part by an effect on the CYP spin state (Reed and Hollenberg 2003a, Reed and Hollenberg 2003b). Its modulatory effect is further supported by the fact that cytochrome b 5 not only increases CYP activity but in some cases also inhibits its activity (Reed and Hollenberg 2003b, Yamaori et al ., 2003).…”

Section: Introductionmentioning

confidence: 99%

Experimental approaches to evaluate activities of cytochromes P450 3A

Bořek-Dohalská¹,

Hodek²,

Hudeček³

et al. 2008

Interdisciplinary Toxicology

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Cytochrome P450 (CYP) is a heme protein oxidizing various xenobiotics, as well as endogenous substrates. Understanding which CYP enzymes are involved in metabolic activation and/or detoxication of different compounds is important in the assessment of an individual's susceptibility to the toxic action of these substances. Therefore, investigation which of several in vitro experimental models are appropriate to mimic metabolism of xenobiotics in organisms is the major challenge for research of many laboratories. The aim of this study was to evaluate the efficiency of different in vitro systems containing individual enzymes of the mixed-function monooxygenase system to oxidize two model substrates of CYP3A enzymes, exogenous and endogenous compounds, α-naphtoflavone (α-NF) and testosterone, respectively. Several different enzymatic systems containing CYP3A enzymes were utilized in the study: (i) human hepatic microsomes rich in CYP3A4, (ii) hepatic microsomes of rabbits treated with a CYP3A6 inducer, rifampicine, (iii) microsomes of Baculovirus transfected insect cells containing recombinant human CYP3A4 and NADPH:CYP reductase with or without cytochrome b5 (Supersomes™), (iv) membranes isolated from of Escherichia coli, containing recombinant human CYP3A4 and cytochrome b5, and (v) purified human CYP3A4 or rabbit CYP3A6 reconstituted with NADPH:CYP reductase with or without cytochrome b5 in liposomes. The most efficient systems oxidizing both compounds were Supersomes™ containing human CYP3A4 and cytochrome b5. The results presented in this study demonstrate the suitability of the supersomal CYP3A4 systems for studies investigating oxidation of testosterone and α-NF in vitro.

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Stimulation of Cytochrome P450 Reactions by Apo-cytochromeb 5

Cited by 95 publications

References 64 publications

Role of Protein–Protein Interactions in Cytochrome P450-Mediated Drug Metabolism and Toxicity

Role of Protein–Protein Interactions in Cytochrome P450-Mediated Drug Metabolism and Toxicity

Regulation of 17,20 Lyase Activity by Cytochrome b5 and by Serine Phosphorylation of P450c17

Experimental approaches to evaluate activities of cytochromes P450 3A

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