Investigating the Mechanism of Trimethoprim-Induced Skin Rash and Liver Injury

Abstract

Trimethoprim (TMP)-induced skin rash and liver injury are likely to involve the formation of reactive metabolites. Analogous to nevirapine-induced skin rash, 1 possible reactive metabolite is the sulfate conjugate of α-hydroxyTMP, a metabolite of TMP. We synthesized this sulfate and found that it reacts with proteins in vitro. We produced a TMP-antiserum and found covalent binding of TMP in the liver of TMP-treated rats. However, we found that α-hydroxyTMP is not a substrate for human sulfotransferases, and we did not detect covalent binding in the skin of TMP-treated rats. Although less reactive than the sulfate, α-hydroxyTMP was found to covalently bind to liver and skin proteins in vitro. Even though there was covalent binding to liver proteins, TMP did not cause liver injury in rats or in our impaired immune tolerance mouse model that has been able to unmask the ability of other drugs to cause immune-mediated liver injury. This is likely because there was much less covalent binding of TMP in the livers of TMP-treated mice than TMP-treated rats. It is possible that some patients have a sulfotransferase that can produce the reactive benzylic sulfate; however, α-hydroxyTMP, itself, has sufficient reactivity to covalently bind to proteins in the skin and may be responsible for TMP-induced skin rash. Interspecies and interindividual differences in TMP metabolism may be 1 factor that determines the risk of TMP-induced skin rash. This study provides important data required to understand the mechanism of TMP-induced skin rash and drug-induced skin rash in general.

Non-innocuous Consequences of Metabolic Oxidation of Alkyls on Arenes

“…The sulfate of 66 was synthesized and, not unexpectedly, was found to react with proteins . However, the authors also found that the alcohol 66 is not a substrate for human SULTs, and they did not detect covalent binding in the skin of TMP-treated rats.…”

Protein Haptenation and Its Role in Allergy

“…Another possible phase II activating interaction involves sulfotransferases or UGTs, also part of the phase II panel of metabolizing, and mainly detoxifying mechanisms. 116 It is thought that sulfotransferases, which are present and active in skin, unlike many other metabolic enzymes, are responsible for activating phase I metabolites of nevirapine. 117 It is hypothesized that lamotrigine, valdecoxib, and sertraline cause skin rash via a reaction that forms a reactive sulfate metabolite in skin (Figure 6A).…”

Bioactivation and reactivity research advances – 2022 year in review‡

“…Yet it has significant side effects including skin reactions and in some rare cases, liver injuries (Lai et al 1999). The general thought is that these injuries could be due to formation of reactive metabolites, and the investigators examined this concept with the focus on bioactivation of trimethoprim (Cao et al 2021). One hypothesis was that a primary metabolite of TMP, mainly a-hydroxyTMP (TMP-OH; Figure 6(a)), formed an electrophillic sulfate metabolite (TMP-S; Figure 6(a)) and would then react with cellular protein to form adducts (called haptens).…”