Aryl Hydrocarbon Hydroxylases

Publication Title: 
British Journal of Clinical Pharmacology

AIMS: The study aimed to identify the specific human cytochrome P450 (CYP450) enzymes involved in the metabolism of artemisinin. METHODS: Microsomes from human B-lymphoblastoid cell lines transformed with individual CYP450 cDNAs were investigated for their capacity to metabolize artemisinin. The effect on artemisinin metabolism in human liver microsomes by chemical inhibitors selective for individual forms of CYP450 was investigated.

Svensson, U. S.
Ashton, M.
Publication Title: 
Tropical medicine & international health: TM & IH

Recently, Ghana has changed the first-line treatment of uncomplicated malaria from chloroquine to amodiaquine (AQ) plus artesunate. AQ may cause adverse events such as agranulocytosis and hepatoxicity. The pro-drug AQ is transformed by cytochrome P450 CYP2C8 to the active metabolite N-desethylaminodiaquine. Several polymorphic variants of CYP2C8 are known, some with reduced activity. In 200 randomly selected children from Northern Ghana, we determined the allele frequencies of the CYP2C8 variants CYP2C8*1 (wild type), CYP2C8*2, CYP2C8*3, and CYP2C8*4.

Röwer, Susanne
Bienzle, Ulrich
Weise, Alexander
Lambertz, Ulrike
Forst, Thomas
Otchwemah, Rowland N.
Pfützner, Andreas
Mockenhaupt, Frank P.
Publication Title: 
European Journal of Clinical Pharmacology

OBJECTIVE: Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of artemisinin drugs, a novel series of antimalarials. Our aim was to analyze the prevalence of the most commonly observed CYP2B6 alleles in malaria-endemic populations of West Africa (WA) and Papua New Guinea (PNG). METHODS: Using a post-PCR ligation detection reaction-fluorescent microsphere assay, frequencies of CYP2B6*1A, *2, *3, *4, *5, *6, *7, and *9 were determined in WA (n=166) and PNG (n=174).

Mehlotra, Rajeev K.
Ziats, Mark N.
Bockarie, Moses J.
Zimmerman, Peter A.
Publication Title: 
Antimicrobial Agents and Chemotherapy

Artesunate (AS) is used in combination with amodiaquine (AQ) as first-line treatment for uncomplicated malaria in many countries. We investigated the effect of concomitant AS administration on the pharmacokinetics of AQ and compared concentrations of desethylamodiaquine (DEAQ), the main metabolite of AQ, in plasma between patients with different variants of the cytochrome P4502C8 (CYP2C8) gene.

Adjei, George O.
Kristensen, Kim
Goka, Bamenla Q.
Hoegberg, Lotte C. G.
Alifrangis, Michael
Rodrigues, Onike P.
Kurtzhals, Jorgen A. L.
Publication Title: 
PloS One

BACKGROUND: Chlorproguanil-dapsone (Lapdap), developed as a low-cost antimalarial, was withdrawn in 2008 after concerns about safety in G6PD deficient patients. This trial was conducted in 2004 to evaluate the safety and effectiveness of CD and comparison with artemether-lumefantrine (AL) under conditions of routine use in G6PD normal and G6PD deficient patients with uncomplicated malaria in The Gambia. We also examined the effects of a common genetic variant that affects chlorproguanil metabolism on risk of treatment failure.

Dunyo, Samuel
Sirugo, Giorgio
Sesay, Sanie
Bisseye, Cyrille
Njie, Fanta
Adiamoh, Majidah
Nwakanma, Davis
Diatta, Mathurin
Janha, Ramatoulie
Sisay Joof, Fatou
Temple, Beth
Snell, Paul
Conway, David
Walton, Robert
Cheung, Yin Bun
Milligan, Paul
Publication Title: 
Drug Metabolism and Disposition: The Biological Fate of Chemicals

Artemether (AM) is one of the most effective antimalarial drugs. The elimination half-life of AM is very short, and it shows large interindividual variability in pharmacokinetic parameters. The aim of this study was to identify cytochrome P450 (P450) isozymes responsible for the demethylation of AM and to evaluate functional differences between 26 CYP2B6 allelic variants in vitro. Of 14 recombinant P450s examined in this study, CYP2B6 and CYP3A4 were primarily responsible for production of the desmethyl metabolite dihydroartemisinin.

Honda, Masashi
Muroi, Yuka
Tamaki, Yuichiro
Saigusa, Daisuke
Suzuki, Naoto
Tomioka, Yoshihisa
Matsubara, Yoichi
Oda, Akifumi
Hirasawa, Noriyasu
Hiratsuka, Masahiro
Publication Title: 
Tropical medicine & international health: TM & IH

Amodiaquine (AQ) is a 4-aminoquinoline widely used in the treatment of malaria as part of the artemisinin combination therapy (ACT). AQ is metabolised towards its main metabolite desethylamodiaquine mainly by cytochrome P450 2C8 (CYP2C8). CYP1A1 and CYP1B1 play a minor role in the metabolism but they seem to be significantly involved in the formation of the short-lived quinine-imine.

Cavaco, I.
Piedade, R.
Msellem, M. I.
Bjorkman, A.
Gil, J. P.
Publication Title: 
Drug Metabolism and Disposition: The Biological Fate of Chemicals

Artemisinin drugs have become the first-line antimalarials in areas of multidrug resistance. However, monotherapy with artemisinin drugs results in comparatively high recrudescence rates. Autoinduction of cytochrome P450 (P450)-mediated metabolism, resulting in reduced exposure, has been supposed to be the underlying mechanism.

Xing, Jie
Kirby, Brian J.
Whittington, Dale
Wan, Yakun
Goodlett, David R.
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

CYP2A6, CYP2B6, and UGT1A9 genetic polymorphisms and treatment response after a three-day course of artesunate-mefloquine was investigated in 71 Burmese patients with uncomplicated Plasmodium falciparum malaria. Results provide evidence for the possible link between CYP2A6 and CYP2B6 polymorphisms and plasma concentrations of artesunate/dihydroartemisinin and treatment response.

Phompradit, Papichaya
Muhamad, Poonuch
Cheoymang, Anurak
Na-Bangchang, Kesara
Publication Title: 
The Journal of Pharmacology and Experimental Therapeutics

Guggulsterone is the active ingredient in gugulipid, an organic extract of the Commiphora mukul plant. Gugulipid has been used for nearly 3000 years in Ayurvedic medicine, mainly as a treatment for arthritis. Herbal practitioners currently use gugulipid therapy in conditions as diverse as rheumatism, coronary artery disease, arthritis, hyperlipidemia, acne, and obesity. The active ingredient in gugulipid is guggulsterone, a plant sterol compound recently identified as a pregnane X receptor (PXR; NR1I2) ligand.

Ding, Xunshan
Staudinger, Jeff L.


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