The effect of tacrolimus-induced toxicity on metabolic profiling in target tissues of mice

Abstract

Tacrolimus (Tac) is a common immunosuppressant that used in organ transplantation. However, its therapeutic index is narrow, and it is prone to adverse side effects, along with an increased risk of toxicity, namely, cardio-, nephro-, hepato-, and neurotoxicity. Prior metabolomic investigations involving Tac-driven toxicity primarily focused on changes in individual organs. However, extensive research on multiple matrices is uncommon. Hence, in this research, the authors systemically evaluated Tac-mediated toxicity in major organs, namely, serum, brain, heart, liver, lung, kidney, and intestines, using gas chromatography−mass spectrometry (GC-MS). The authors also employed multivariate analyses, including orthogonal projections to the latent structure (OPLS) and t-test, to screen 8 serum metabolites, namely, D-proline, glycerol, D-fructose, D-glucitol, sulfurous acid, 1-monopalmitin (MG (16:0/0:0/0:0)), glycerol monostearate (MG (0:0/18:0/0:0)), and cholesterol. Metabolic changes within the brain involved alterations in the levels of butanamide, tartronic acid, aminomalonic acid, scyllo-inositol, dihydromorphine, myo-inositol, and 11-octadecenoic acid. Within the heart, the acetone and D-fructose metabolites were altered. In the liver, D-glucitol, L-sorbose, palmitic acid, myo-inositol, and uridine were altered. In the lung, L-lactic acid, L-5-oxoproline, L-threonine, phosphoric acid, phosphorylethanolamine, D-allose, and cholesterol were altered. Lastly, in the kidney, L-valine and D-glucose were altered. Our findings will provide a systematic evaluation of the metabolic alterations in target organs within a Tac-driven toxicity mouse model.

Metabolomic Profiling of Mice with Tacrolimus-Induced Nephrotoxicity: Carnitine Deficiency in Renal Tissue

“…Since TAC-induced nephrotoxicity of renal allotransplantation is chronic kidney injury, it is important to understand the pathophysiology and mechanism using a chronic TAC nephrotoxicity model. Although there has been only one report of metabolite analyses in multiple organs of mice treated with TAC for 2 weeks, only two metabolites showed significant changes in kidney tissue [ 17 ]. In addition, that report did not identify any histological changes associated with kidney injury.…”

Vancomycin relieves tacrolimus-induced hyperglycemia by eliminating gut bacterial beta-glucuronidase enzyme activity

“… 15 TAC induces toxicity via its drug prototype rather than metabolites. 16 , 17 Whether alterations in endogenous metabolite or exogenous drug exposure induced by UGTs would impact the toxicity of TAC remains unclear. 18 GUS enzyme is closely related to the hydrolysis of glucuronides and glucose metabolism.…”