Studies on the Metabolism and Biological Activity of the Epimers of Sulindac

Abstract

ABSTRACT:Sulindac is a nonsteroidal, anti-inflammatory drug (NSAID) that has also been studied for its anticancer activity. Recent studies suggest that sulindac and its metabolites act by sensitizing cancer cells to oxidizing agents and drugs that affect mitochondrial function, resulting in the production of reactive oxygen species and death by apoptosis. In contrast, normal cells are not killed under these conditions and, in some instances, are protected against oxidative stress. Sulindac has a methyl sulfoxide moiety with a chiral center and was used in all of the previous studies as a mixture of the R-and S-epimers. Because epimers of a compound can have very different chemical and biological properties, we have separated the R-and S-epimers of sulindac, studied their individual metabolism, and performed preliminary experiments on their effect on normal and lung cancer cells exposed to oxidative stress. Previous results had indicated that the reduction of (S)-sulindac to sulindac sulfide, the active NSAID, was catalyzed by methionine sulfoxide reductase (Msr) A. In the present study, we purified an enzyme that reduces (R)-sulindac and resembles MsrB in its substrate specificity. The oxidation of both epimers to sulindac sulfone is catalyzed primarily by the microsomal cytochrome P450 (P450) system, and the individual enzymes responsible have been identified. (S)-Sulindac increases the activity of the P450 system better than (R)-sulindac, but both epimers increase primarily the enzymes that oxidize (R)-sulindac. Both epimers can protect normal lung cells against oxidative damage and enhance the killing of lung cancer cells exposed to oxidative stress.

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“…Sulindac is a prodrug that must be reduced to sulindac sulfide which is the active NSAID. Since sulindac is also a mixture of the R and S epimers the metabolism of both epimers has been recently elucidated as shown in Figure 5 (Brunell et al, 2011). The reduction of the S epimer is catalyzed by MsrA and as seen in Figure 6, the R epimer is reduced by an enzyme in liver that has the properties of MsrB (Brunell et al, 2011).…”

“…Since sulindac is also a mixture of the R and S epimers the metabolism of both epimers has been recently elucidated as shown in Figure 5 (Brunell et al, 2011). The reduction of the S epimer is catalyzed by MsrA and as seen in Figure 6, the R epimer is reduced by an enzyme in liver that has the properties of MsrB (Brunell et al, 2011). Sulindac can also induce the P450 system and be oxidized by the P450 system to sulindac sulfone (Ciolino et al, 2008;Brunell et al, 2011).…”

“…The reduction of the S epimer is catalyzed by MsrA and as seen in Figure 6, the R epimer is reduced by an enzyme in liver that has the properties of MsrB (Brunell et al, 2011). Sulindac can also induce the P450 system and be oxidized by the P450 system to sulindac sulfone (Ciolino et al, 2008;Brunell et al, 2011). Sulindac sulfone is not an NSAID and is not a substrate for the Msr system.…”

“…MsrA has been studied in most detail and shown to protect bacterial and animal cells against oxidative damage (for review see Weissbach et al, 2005). The studies with MsrA led to investigations with the drug sulindac, a known non-steroidal anti-inflammatory drug (NSAID), that is a substrate for the Msr system (Etienne et al 2003;Brunell et al 2011). Sulindac protects the heart against ischemic infarction through a newly described activity as a pharmacological preconditioning agent (Moench et al, 2009).…”

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“…It is a prodrug, composed of R and S epimers, whose NSAID activity is dependent on the reduction of the epimers to sulindac sulfide, the active cyclooxygenase (COX) inhibitor (4). This reduction is catalyzed by two members of the methionine sulfoxide reductase (Msr) family, MsrA and MsrB, that reduce the sulindac S and R epimers, respectively (5). Because substrates of the Msr system, such as methionine sulfoxide in proteins, could theoretically function as part of an ROS scavenger system (6), sulindac was previously tested for its protective effect in cultured normal human lung cells and shown to protect these cells against oxidative damage.…”