scholarly journals Cyclization reactions of IMM-125 and oxidation of cyclosporin A amino-acid 1 in theαposition of the double bond lead to the loss ofin vitroimmunosuppressive activity

2000 ◽  
Vol 14 (4) ◽  
pp. 215-228
Author(s):  
R. Dieden ◽  
D. Latinne ◽  
C. Baldari ◽  
N. Maton ◽  
A. Aubry ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cyclosporin A ◽  
Parent Drug ◽  
Nucleophilic Attack ◽  
Monooxygenase System ◽  
Cyclization Reactions ◽  
Perbenzoic Acid ◽  
Jurkat T Cell ◽  
Cytochrome P 450 ◽  
Hepatic Cytochrome

Cyclosporin A (CsA) and IMM-125, a hydroxyethyl derivative of D-serine CsA, are cyclic undecapeptides of molecular weight 1201.8 and 1261.8, respectively. The main metabolites still possessing the undecapeptide structure were found to be compounds resulting from the biotransformation of amino acids 4, 9 and 1.Under the influence of the hepatic cytochrome P-450-dependent monooxygenase system, CsA and IMM-125 amino acid 1 are metabolized to a mono-hydroxylated compound (metabolite M-17) and to a dihydrodiol. A metabolite M18 was found to be the result of a non-enzymic intramolecular formation of a tetrahydrofuran derivative from metabolite M17. Since the existence of a CsA dihydrodiol was reported and since epoxides are considered as the dihydrodiol precursors, the aim of the present work was to prove that the same non-enzymic intramolecular formation of a tetrahydrofuran ring could occur by nucleophilic attack of the amino-acid 1β-hydroxy group at theɛ-position of the freshly formed epoxide by reaction of IMM-125 with m-chloro-perbenzoic acid and cyclosporin A with selenium oxide. The immunosuppressive activity of the compounds, as measured by the mixed lymphocyte reaction and by the luciferase activity of a Jurkat-T-cell line stably transfected with the NF-AT/luc reporter plasmid, was found negligible for IMM-125 compared to the parent drug as well as for the cyclosporin A derivative. Structures of the IMM-125 and CsA derivatives were elucidated by electrospray mass‒spectrometry and NMR spectroscopy.

scholarly journals Effects of Bromocriptine on Hepatic Cytochrome P-450 Monooxygenase System

1989 ◽  
Vol 49 (2) ◽  
pp. 285-291
Author(s):  
Shabbir M. MOOCHHALA ◽  
Edmund J.D. LEE ◽  
Gwendolene T.M. HU ◽  
O.S. KOH ◽  
Gordon BECKET
Keyword(s):  
Monooxygenase System ◽  
Cytochrome P 450 ◽  
Hepatic Cytochrome

scholarly journals Effects of bromocriptine on hepatic cytochrome P-450 monooxygenase system.

1989 ◽  
Vol 49 (2) ◽  
pp. 285-291 ◽  
Author(s):  
Shabbir M. MOOCHHALA ◽  
Edmund J.D. LEE ◽  
Gwendolene T.M. HU ◽  
O.S. KOH ◽  
Gordon BECKET
Keyword(s):  
Monooxygenase System ◽  
Cytochrome P 450 ◽  
Hepatic Cytochrome

Hepatic cytochrome P-450 reductase-null mice show reduced transcriptional response to quercetin and reveal physiological homeostasis between jejunum and liver

2006 ◽  
Vol 291 (1) ◽  
pp. G63-G72 ◽  
Author(s):  
David M. Mutch ◽  
Vanessa Crespy ◽  
Jennifer Clough ◽  
Colin J. Henderson ◽  
Sofiane Lariani ◽  
...  
Keyword(s):  
Small Intestine ◽  
Fatty Acid ◽  
Amino Acid ◽  
Fatty Acid Metabolism ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Glutathione Metabolism ◽  
Sterol Metabolism ◽  
Cytochrome P 450 ◽  
Hepatic Cytochrome

Using mice deficient in hepatic cytochrome P-450 oxidoreductase (POR), which disables the liver cytochrome P-450 system, we examined the metabolism and biological response of the anticarcinogenic flavonoid, quercetin. Profiling circulating metabolites revealed similar profiles over 72 h in wild-type (WT) and POR-null (KO) mice, showing that hepatic P450 and reduced biliary secretion do not affect quercetin metabolism. Transcriptional profiling at 24 h revealed that two- to threefold more genes responded significantly to quercetin in WT compared with KO in the jejunum, ileum, colon, and liver, suggesting that hepatic P450s mediate many of the biological effects of quercetin, such as immune function, estrogen receptor signaling, and lipid, glutathione, purine, and amino acid metabolism, even though quercetin metabolism is not modified. The functional interpretation of expression data in response to quercetin (single dose of 7 mg/animal) revealed a molecular relationship between the liver and jejunum. In WT animals, amino acid and sterol metabolism was predominantly modulated in the liver, fatty acid metabolism response was shared between the liver and jejunum, and glutathione metabolism was modulated in the small intestine. In contrast, KO animals do not regulate amino acid metabolism in the liver or small intestine, they share the control of fatty acid metabolism between the liver and jejunum, and regulation of sterol metabolism is shifted from the liver to the jejunum and that of glutathione metabolism from the jejunum to the liver. This demonstrates that the quercetin-mediated regulation of these biological functions in extrahepatic tissues is dependent on the functionality of the liver POR. In conclusion, using a systems biology approach to explore the contribution of hepatic phase 1 detoxification on quercetin metabolism demonstrated the resiliency and adaptive capacity of a biological organism in dealing with a bioactive nutrient when faced with a tissue-specific molecular dysfunction.

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