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. 1999 Jun 22;96(13):7563-8.
doi: 10.1073/pnas.96.13.7563.

Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis

T D Warner  1 , F Giuliano, I Vojnovic, A Bukasa, J A Mitchell, J R Vane
Affiliations

Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis

T D Warner et al. Proc Natl Acad Sci U S A. .

Erratum in

  • Proc Natl Acad Sci U S A 1999 Aug 17;96(17):9666

Abstract

The beneficial actions of nonsteroid anti-inflammatory drugs (NSAID) can be associated with inhibition of cyclo-oxygenase (COX)-2 whereas their harmful side effects are associated with inhibition of COX-1. Here we report data from two related assay systems, the human whole blood assay and a modified human whole blood assay (using human A549 cells as a source of COX-2). This assay we refer to as the William Harvey Modified Assay. Our aim was to make meaningful comparisons of both classical NSAIDs and newer COX-2-selective compounds. These comparisons of the actions of >40 NSAIDs and novel COX-2-selective agents, including celecoxib, rofecoxib and diisopropyl fluorophosphate, demonstrate a distribution of compound selectivities toward COX-1 that aligns with the risk of serious gastrointestinal complications. In conclusion, this full in vitro analysis of COX-1/2 selectivities in human tissues clearly supports the theory that inhibition of COX-1 underlies the gastrointestinal toxicity of NSAIDs in man.

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Figures

Figure 1
Figure 1
The effects of celecoxib (A), diclofenac (B), etodolac (C), ibuprofen (D), meloxicam (E), and nimesulide (F) on the activity of COX-1 (solid line), WBA-COX-2 (short dashed line), and WHMA-COX-2 (long dashed line). Results are expressed as percent of control and are represented as mean ± SEM. (n = 5–8).
Figure 2
Figure 2
The effects of diisopropyl fluorophosphate (A), L-745,337 (B), NS398 (C), and rofecoxib (D) on the activity of COX-1 (solid line), WBA-COX-2 (short dashed line), and WHMA-COX-2 (long dashed line). Results are expressed as percent of control and are represented as mean ± SEM. (n = 5–8).
Figure 3
Figure 3
Determinable log [IC80 ratio (WBA-COX-2/COX-1)] for all agents assayed (see Table 1). The “0 line” indicates equipotency, i.e., an IC80 ratio of 1. Italics indicate compounds with very low potency.
Figure 4
Figure 4
Analysis of the percent inhibition of COX-1 seen when COX-2 (WHMA) is inhibited by 80%. The dotted line indicates equiactivity, i.e., an 80% inhibition of COX-1.
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