Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Abstract

Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

Genetic polymorphisms of cytochrome P450 enzymes 2C9 and 2C19 in a healthy Mongolian population in China

“…CYP2C9 catalyses the oxidation of clinically important drugs including phenytoin, tolbutamide, warfarin, and a large number of nonsteroidal anti-inflammatory drugs (Miners and Birkett, 1998;Zhou et al, 2009b;Kesavan et al, 2010). Presently, 34 different CYP2C9 allelic variants have been identified (http://www.cypalleles.ki.se/cyp2c9.htm, January 2009).…”

Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450

“…Oxidation by P450s can lead to toxic products, but, on the other hand, local activation of, e.g., anticancer prodrugs by P450s to lethal intracellular toxins at the site of the tumor is an important strategy (1). Drug compounds can induce P450 expression but can also inhibit them in various ways (2)(3)(4). The metabolic clearance of most drugs depends on P450s, and they have been implicated in a large number of drug-drug interactions (5,6), which can result in fatalities (7,8).…”

Pharmacogenetics of nonsteroidal anti-inflammatory drugs

“…24 As stated earlier, celecoxib is extensively metabolized by CYP2C9. 25 An in vitro study utilizing human liver microsomes in addition to yeast microsomes expressing a number of CYP polymorphisms showed that CYP2C9*3 had a lower intrinsic clearance of celecoxib when compared with the wild-type CYP2C9*1 samples. 26 There are conflicting results about whether CYP2C9*2 has a significant decrease in intrinsic clearance.…”

“…22 Naproxen sodium is metabolized by the liver enzyme CYP2C9 forming 6-desmethylnaproxen. 25 Like flurbiprofen, the CYP2C9*3 and CYP2C9*5 alleles show a lower clearance when compared with the wild-type CYP2C9*1. 18 However, another study assessed the role of CYP2C9 in the overall clearance of naproxen and concluded that CYP2C9 played a minor role in naproxen clearance, suggesting that pharmacogenetic differences would not be clinically significant if compromised CYP2C9 activity was possessed by a patient taking this medication.…”