Metabolism and Biological Activity of Sulindac and its Epimers

Sulindac can be oxidized to sulindac sulfone and reduced to sulindac sulfide, an active cyclooxygenase (COX) inhibitor. However, the metabolism and biological activities of the individual R and S epimers are not known. In vivo, the R epimer yielded higher plasma levels of the sulfone, whereas the S epimer was more readily reduced to the sulfide. In a hepatoma cell line, both epimers activated the aryl hydrocarbon receptor and significantly induced cytochrome P450 enzymes. The R epimer was oxidized to sulindac sulfone more readily than the S epimer. A rat liver cell extract reduced both the R and S epimers of sulindac with either DTT or thioredoxin. The S epimer is primarily reduced by methionine sulfoxide reductase A (MsrA). The enzyme(s) responsible for reduction of the R epimer has been partially purified. Sulindac enhances killing of human colon, skin, and lung cancer cells by oxidative stress. The effect does not involve COX inhibition or the Msr system. An increase in reactive oxygen species (ROS) and loss of mitochondrial membrane potential suggest that cell death is due to apoptosis. Both epimers were effective under the conditions used. In contrast, no enhanced killing was observed using either epimer with normal cells under the same conditions. In summary it appears that the R and S epimers of sulindac are metabolized by different pathways and that these epimers may have different pharmacological properties.