Involvement of microsomal NADPH‐cytochrome P450 reductase in metabolic reduction of drug ketones

Abstract

Recently, it was found that the carbonyl group of 1-[3-(4-phenoxyphenoxy)-2-oxopropyl]indole-5-carboxylic acid (5), an inhibitor of the pro-inflammatory enzyme cytosolic phospholipase A α, is easily reduced by rat liver S9 fractions in vitro. Determination of the inhibitory potency of certain putative inhibitors of carbonyl reducing enzymes on the transformation of the ketone derivative 5 to its alcohol 6 by recombinant microsomal NADPH-cytochrome P450 reductase and by recombinant cytosolic carbonyl reductase-1 now reveals that these compounds show a lack of specificity for these two enzymes in part. Thus, an assignment of the roles of different carbonyl reductases in metabolic keto reduction by the use of inhibitors is problematic. In addition, the ability of NADPH-cytochrome P450 reductase and carbonyl reductase-1 to reduce the ketone groups of the drugs haloperidol and daunorubicin was examined. Under the conditions applied, a pronounced reductive metabolism was only observed for daunorubicin in the presence of microsomal NADPH-cytochrome P450 reductase. Similarly, in rat liver S9 fractions a marked reduction of daunorubicin was seen, while haloperidol was only slightly metabolized to its alcohol. After separation of the S9 homogenate into a microsomal and a cytosolic fraction, it became evident that the ketone groups of daunorubicin, haloperidol and compound 5 were mainly reduced by cytosolic enzymes. However, since microsomes also catalysed these carbonyl reductions to some extent, it can be concluded that microsomal NADPH-cytochrome P450 reductase can contribute to metabolic keto reductions in xenobiotics. Copyright © 2015 John Wiley & Sons, Ltd.

Synthesis, activity and metabolic stability of propan-2-one substituted tetrazolylalkanoic acids as dual inhibitors of cytosolic phospholipase A2α and fatty acid amide hydrolase

“…bPercent of parent remaining after incubation with rat liver S9 fraction for 30 min in presence of the co-factor NADPH; values are means of independent duplicates; metabolic stability of the reference daunorubicin: 28 ± 4% ( n = 6). 35 …”

“…However, when NADPH is added after preincubation, the inhibition strength is reduced due to a reduction of the ketones to inactive alcohols by carbonyl reductases present in the liver preparation, 23 indicating the reversibility of the covalent inhibition. Due to the susceptibility of the ketone function to metabolic reduction by carbonyl reductases 35,36 we have also examined all target structures for metabolic stability in rat liver S9 fraction in presence of NADPH. 23,32 Under the experimental conditions, nearly all compounds were almost completely metabolised to the appropriate alcohols.…”

“…Inhibition of cPLA 2 α and FAAH and metabolic stability in rat liver S9 fraction Values are the means of at least two independent determinations, errors are within ±20%. b Percent of parent remaining after incubation with rat liver S9 fraction for 30 min in presence of the co-factor NADPH; values are means of independent duplicates; metabolic stability of the reference daunorubicin: 28 ± 4% (n = 6) 35. c 39% inhibition at 10 μM.…”

Metabolism of F18, a Derivative of Calanolide A, in Human Liver Microsomes and Cytosol

“…Quercetin, a CBR1 inhibitor (Atalla et al, 2000 ; Rosemond and Walsh, 2004 ), significantly inhibited the formation of M3-1 and M3-2, indicating that CBR1 is involved in F18 metabolism. Menadione, another CBR inhibitor that reportedly does not affect the activity of CBR1, can also inhibit the carbonyl reduction of F18 (Lehr et al, 2015 ). Thus, CBR3 might also participate in the formation of M3-1 and M3-2.…”