Cytochrome P450 systems—biological variations of electron transport chains

Hannemann, Frank; Bichet, Andreas; Ewen, Kerstin Maria; Bernhardt, Rita

doi:10.1016/j.bbagen.2006.07.017

Cited by 676 publications

(522 citation statements)

References 168 publications

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“…Hence their ubiquitous presence throughout all species where hundreds of isoforms have evolved to catalyze a countless number of substrates [1,2].…”

Section: Introductionmentioning

confidence: 99%

“…Whereas the liver clearly contains the highest content of total P450s, isoforms are expressed in kidney, gut, lung, skin, placenta, blood vessels and likely every cell in every organ system [1][2][3]. These extra hepatic tissues are often the target sites for therapeutic intervention against localized pathologies like cancer, infections and inflammations that coincidentally can result in toxicities arising from the biotransformation of the administered drug(s) [3,4].…”

Section: Introductionmentioning

confidence: 99%

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Sex-dependent expression of CYP2C11 in spleen, thymus and bone marrow regulated by growth hormone

Thangavel

Dhir

Volgin

et al. 2007

Biochemical Pharmacology

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CYP2C11, the most commonly expressed isoform of cytochrome P450 in male rat liver, was measured in spleen, thymus and bone marrow by quantitative real-time PCR and enhanced Western blotting. CYP2C11 concentrations in the lymphoid tissues were a fraction of that observed in liver, but like the liver, were sexually dimorphic (M>F) with mRNA and protein levels in agreement. Although the response to hypophysectomy varied according to tissue and sex, expression levels of CYP2C11 in all measured tissues remained greater in males. Further differences in CYP2C11 expression between liver and lymphoid tissue were observed following restoration of the circulating masculine growth hormone profile in hypophysectomized rats. In contrast to the liver where the renaturalized growth hormone profile elevated CYP2C11 expression in both sexes, the response was opposite in spleen and thymus with isoform concentrations declining in both sexes. Lastly, the divergent response of CYP2C11 between the liver and immune system was examined in cultured splenocytes exposed to different mitogens. In contrast to the dramatic depletion of CYP2C11 reported in proliferating hepatocytes, mitogen-stimulation resulted in a significant elevation in splenocyte CYP2C11 expression. In summary, we report for the first time that thymus, spleen and bone marrow express, albeit nominal, sex-dependent levels of CYP2C11 (M>F) whose regulation appears to be under some hormonal control, but very different from that of the hepatic isoform.

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“…Hence their ubiquitous presence throughout all species where hundreds of isoforms have evolved to catalyze a countless number of substrates [1,2].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sex-dependent expression of CYP2C11 in spleen, thymus and bone marrow regulated by growth hormone

Thangavel

Dhir

Volgin

et al. 2007

Biochemical Pharmacology

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“…Since P450 enzymes are monooxygenases, they require electrons from NADPH, which are transferred by autologous or heterologous redox partners (Hannemann et al, 2007). The substrate turnover also depends on the coupling and the efficiency of the redox partner proteins.…”

Section: Optimization Of the In Vitro Conversionmentioning

confidence: 99%

CYP267A1 and CYP267B1 from Sorangium cellulosum So ce56 are Highly Versatile Drug Metabolizers

Kern

Khatri

Litzenburger

et al. 2016

Drug Metabolism and Disposition

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The guidelines of the Food and Drug Administration and International Conference on Harmonization have highlighted the importance of drug metabolites in clinical trials. As a result, an authentic source for their production is of great interest, both for their potential application as analytical standards and for required toxicological testing. Since we have previously shown promising biotechnological potential of cytochromes P450 from the soil bacterium Sorangium cellulosum So ce56, herein we investigated the CYP267 family and its application for the conversion of commercially available drugs including nonsteroidal anti-inflammatory, antitumor, and antihypotensive drugs. The CYP267 family, especially CYP267B1, revealed the interesting ability to convert a broad range of substrates. We established substrate-dependent extraction protocols and also optimized the reaction conditions for the in vitro experiments and Escherichia coli-based whole-cell bioconversions. We were able to detect activity of CYP267A1 toward seven out of 22 drugs and the ability of CYP267B1 to convert 14 out of 22 drugs. Moderate to high conversions (up to 85% yield) were observed in our established whole-cell system using CYP267B1 and expressing the autologous redox partners, ferredoxin 8 and ferredoxin-NADP + reductase B. With our existing setup, we present a system capable of producing reasonable quantities of the human drug metabolites 49-hydroxydiclofenac, 2-hydroxyibuprofen, and omeprazole sulfone. Due to the great potential of converting a broad range of substrates, wild-type CYP267B1 offers a wide scope for the screening of further substrates, which will draw further attention to future biotechnological usage of CYP267B1 from S. cellulosum So ce56.

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“…Microbial CYPs have revealed diverse classes [36] that will be useful in biotechnology. Ten classes have currently been assigned.…”

Section: Microbial Cytochromes P450 and Their Electron Donorsmentioning

confidence: 99%

Microbial cytochromes P450: biodiversity and biotechnology. Where do cytochromes P450 come from, what do they do and what can they do for us?

Kelly

2013

Phil. Trans. R. Soc. B

181

131

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The first eukaryote genome revealed three yeast cytochromes P450 (CYPs), hence the subsequent realization that some microbial fungal genomes encode these proteins in 1 per cent or more of all genes (greater than 100) has been surprising. They are unique biocatalysts undertaking a wide array of stereo-and regio-specific reactions and so hold promise in many applications. Based on ancestral activities that included 14a-demethylation during sterol biosynthesis, it is now seen that CYPs are part of the genes and metabolism of most eukaryotes. In contrast, Archaea and Eubacteria often do not contain CYPs, while those that do are frequently interesting as producers of natural products undertaking their oxidative tailoring. Apart from roles in primary and secondary metabolism, microbial CYPs are actual/potential targets of drugs/agrochemicals and CYP51 in sterol biosynthesis is exhibiting evolution to resistance in the clinic and the field. Other CYP applications include the first industrial biotransformation for corticosteroid production in the 1950s, the diversion into penicillin synthesis in early mutations in fungal strain improvement and bioremediation using bacteria and fungi. The vast untapped resource of orphan CYPs in numerous genomes is being probed and new methods for discovering function and for discovering desired activities are being investigated.

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Cytochrome P450 systems—biological variations of electron transport chains

Cited by 676 publications

References 168 publications

Sex-dependent expression of CYP2C11 in spleen, thymus and bone marrow regulated by growth hormone

Sex-dependent expression of CYP2C11 in spleen, thymus and bone marrow regulated by growth hormone

CYP267A1 and CYP267B1 from Sorangium cellulosum So ce56 are Highly Versatile Drug Metabolizers

Microbial cytochromes P450: biodiversity and biotechnology. Where do cytochromes P450 come from, what do they do and what can they do for us?

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