ABSTRACT:Several antihistamine drugs including terfenadine, ebastine, and astemizole have been identified as substrates for CYP2J2. The overall importance of this enzyme in drug metabolism has not been fully explored. In this study, 139 marketed therapeutic agents and compounds were screened as potential CYP2J2 substrates. Eight novel substrates were identified that vary in size and overall topology from relatively rigid structures (amiodarone) to larger complex structures (cyclosporine). The substrates displayed in vitro intrinsic clearance values ranging from 0.06 to 3.98 l/min/pmol CYP2J2. Substrates identified for CYP2J2 are also metabolized by CYP3A4. Extracted ion chromatograms of metabolites observed for albendazole, amiodarone, astemizole, thioridazine, mesoridazine, and danazol showed marked differences in the regioselectivity of CYP2J2 and CYP3A4. CYP3A4 commonly metabolized compounds at multiple sites, whereas CYP2J2 metabolism was more restrictive and limited, in general, to a single site for large compounds. Although the CYP2J2 active site can accommodate large substrates, it may be more narrow than CYP3A4, limiting metabolism to moieties that can extend closer toward the active heme iron. For albendazole, CYP2J2 forms a unique metabolite compared with CYP3A4. Albendazole and amiodarone were evaluated in various in vitro systems including recombinant CYP2J2 and CYP3A4, pooled human liver microsomes (HLM), and human intestinal microsomes (HIM). The Michaelis-Menten-derived intrinsic clearance of N-desethyl amiodarone was 4.6 greater in HLM than in HIM and 17-fold greater in recombinant CYP3A4 than in recombinant CYP2J2. The resulting data suggest that CYP2J2 may be an unrecognized participant in first-pass metabolism, but its contribution is minor relative to that of CYP3A4.
ABSTRACT:CYP2J2, an arachidonic acid epoxygenase, is recognized for its role in the first-pass metabolism of astemizole and ebastine. To fully assess the role of CYP2J2 in drug metabolism, a selective substrate and potent specific chemical inhibitor are essential. In this study, we report amiodarone 4-hydoxylation as a specific CYP2J2-catalyzed reaction with no CYP3A4, or other drug-metabolizing enzyme, involvement. Amiodarone 4-hydroxylation enabled the determination of liver relative activity factor and intersystem extrapolation factor for CYP2J2. Amiodarone 4-hydroxylation correlated with astemizole O-demethylation but not with CYP2J2 protein content in a sample of human liver microsomes. To identify a specific CYP2J2 inhibitor, 138 drugs were screened using terfenadine and astemizole as probe substrates with recombinant CYP2J2. Forty-two drugs inhibited CYP2J2 activity by >50% at 30 M, but inhibition was substrate-dependent. Of these, danazol was a potent inhibitor of both hydroxylation of terfenadine (IC 50 ؍ 77 nM) and O-demethylation of astemizole (K i ؍ 20 nM), and inhibition was mostly competitive. Danazol inhibited CYP2C9, CYP2C8, and CYP2D6 with IC 50 values of 1.44, 1.95, and 2.74 M, respectively. Amiodarone or astemizole were included in a sevenprobe cocktail for cytochrome P450 (P450) drug-interaction screening potential, and astemizole demonstrated a better profile because it did not appreciably interact with other P450 probes. Thus, danazol, amiodarone, and astemizole will facilitate the ability to determine the metabolic role of CYP2J2 in hepatic and extrahepatic tissues.
Objectives-The calcineurin inhibitors (CNIs) cyclosporine A (CsA) and tacrolimus (Tac) help prevent allograft rejection but are associated with nephrotoxicity. Cytochrome P450 2C8 (CYP2C8) and CYP2J2 are polymorphic enzymes expressed in the kidney that metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids, promoting kidney homeostasis. This study examined the association between CNI-induced nephrotoxicity in liver transplant patients and CYP2C8 and CYP2J2 polymorphisms.Methods-Liver transplantation patients receiving CNIs for at least three years were genotyped for CYP2C8*3, CYP2C8*4, CYP2C8 Haplotypes B and C, and CYP2J2*7 and evaluated for nephrotoxicity (serum creatinine ≥ 1.6 mg/dL) three-years post-transplantation. CYP2C8 proteins were also engineered in E. coli and their activity towards AA and inhibition by CNIs was investigated in vitro.
The intramolecular isotope effect for the cytochrome P-450b -hydroxylation of [1,1,1-2H3]-«-octane was separated into its primary and secondary components by the method of Hanzlik (Hanzlik et al. J. Am. Chem. Soc. 1985, 107, 7164). The primary isotope effect was found to lie between 7.3 and 7.9 while the secondary isotope effect was found to lie between 1.09 and 1.14. These data are consistent with a highly symmetrical transition state with 15% of the observed isotope effect being due to secondary isotope effects. Although the system was found to depart from the rule of the geometric mean, the phenomenon could not be attributed to tunneling.
Purpose -The total quality management (TQM) concept was originally developed to increase the efficiency of occidental and Japanese organisations. As a consequence of its success there, it has spread world-wide. Companies in many developing countries are attempting its implementation. However, the cultural environment in these countries may be significantly different from the prevalent one in the regions where TQM has flourished. This paper aims to examine the potential for successful TQM implementation in a "theoretically" unfavourable TQM environment, and what can be expected from such implementation if it is successful. Design/methodology/approach -This study is based on a case of a company with characteristics that are in conflict with what are accepted to be necessary for successful implementation of TQM. The development of TQM in the company is examined and successes and failures in the implementation process they implemented are evaluated. The degree of success in implementing TQM is assessed through the changes that resulted in both internal performance indicators and an independent external governmental evaluation of the company. Findings -It is possible to implement TQM principles in an environment deficient in factors that are generally accepted as critical to its successful implementation. The identification of and reaction to cultural difficulties are central to a successful TQM implementation approach taken. Positive outcomes may exceed, in terms of speed and scale, what could be expected from the occidental/Japanese model for successful TQM implementation. Research limitations/implications -As the research is based on a specific case study, it does not provide a proof that all companies in unfavourable environments can benefit from TQM implementation. Originality/value -Very little research is currently available about TQM implementation in unfavourable environments, about how to deal with these specificities, and what benefits can realistically be expected if the implementation is successful.
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