New insights into ethionamide metabolism: influence of oxidized methionine on its degradation path

Abstract

Ethionamide (ETH) is a commercial drug, used as a second-line resource to neutralize Mycobacterium tuberculosis infections. It is proven that its metabolization in the organism leads to the formation of the active form of the drug, but some metabolic pathways may lead to the loss of its activity. Our work proved that the presence of oxidized methionine in cells could influence ETH's degradation, leading to the appearance of an inactive metabolite that is detectable by HPLC and mass spectrometry. In addition, it was found this process increases with the degree of methionine oxidation. This study contributes to a better understanding of ethionamide's metabolism in living organisms, and can help in the design of new drugs or ethionamide boosters for the combat of multidrug resistant tuberculosis.

Scheme 1. Structure of ETH (1) and its reported oxidation metabolites: ETH-SO (active) (2) and inactive metabolites (3–5).

Scheme 2. Mechanism of methionine oxidation, leading to metabolites MetSO and MetSO₂.

Fig. 1. Relative abundance of the ETH carbonitrile inactive metabolite in HepG2 cells treated with ETH alone or in the presence of 2 mM of Met, MetSO and MetSO₂ after 3 h.

Scheme 3. ETH's degradation is induced by methionine oxidation, resulting in the formation of inactive metabolites with less therapeutic index.

Scheme 4. Proposed mechanism for ETH metabolic activation leading to the formation of non-active metabolites in the presence of Met/Met-SO or Met-SO₂.