Carbamazepine-induced liver injury using type 2 diabetes Spontaneously Diabetic Torii-<i>Lepr^fa</i> (SDT fatty) rats as a model for human type 2 diabetes

Abstract

The diabetic state is considered to be one of the risk factors of drug-induced liver injury (DILI) because of the lower levels of glutathione for detoxification by conjugation with drugs. Carbamazepine (CBZ)-induced hepatotoxicity in humans is rare and unpredictable with the present state of knowledge, but it is somehow related to disturbance of glutathione metabolism, although data in this regard are limited. In order to estimate the potential risk of DILI in patients with type 2 diabetes mellitus (T2DM), we investigated the liver injury from CBZ, which is often used in the treatment of painful diabetic neuropathy in diabetic patients, using SD rats and Spontaneously Diabetic Torii-Lepr fa (SDT fatty) rats as a model for human T2DM. The SDT fatty rats appropriately mimic the diabetic state in humans and have similar profiles of glucose metabolism, hepatic function tests and glutathione synthesis to those in patients with T2DM. Short-term oral dosing with CBZ to the SDT fatty rats revealed that liver injury was detected in the SDT fatty rats but not in the SD rats and the difference was considered to be due to lower hepatic detoxification of the metabolites of CBZ by depleted hepatic glutathione synthesis. In conclusion, the potential for CBZ to induce liver injury is considered to be higher in diabetic patients than in non-diabetic humans.

Comparison of the liver findings after simvastatin-treatment between Spontaneously Diabetic Torii-<i>Lepr</i><i>^fa</i> (SDT fatty) rats and Sprague-Dawley rats

“…Our previous investigation revealed that the SDT fatty rats have lower levels of hepatic GSH and GSSG, and the characteristics of glucose metabolism, liver function and hepatic glutathione synthesis in the SDT fatty rats are like those in T2DM patients (Takahashi et al, 2019a). In addition, allyl alcohol and carbamazepine induced liver injury more prominently in the SDT fatty rats than in the SD rats (Takahashi et al, 2019a(Takahashi et al, , 2019b. From these, the potential for allyl alcohol and carbamazepine to induce liver injury was assessed to be higher in diabetic patients than in non-diabetics (Takahashi et al, 2019a(Takahashi et al, , 2019b.…”

“…In addition, allyl alcohol and carbamazepine induced liver injury more prominently in the SDT fatty rats than in the SD rats (Takahashi et al, 2019a(Takahashi et al, , 2019b. From these, the potential for allyl alcohol and carbamazepine to induce liver injury was assessed to be higher in diabetic patients than in non-diabetics (Takahashi et al, 2019a(Takahashi et al, , 2019b. In the present study, we investigated the potential of simvastatin to induce DILI using the SDT fatty rats to estimate the risk of DILI in diabetic patients because simvastatin is used in diabetic patients and shows a positive higher reaction in a GSH adduct assay in vitro (Sakatis et al, 2012) although major metabolic pathway for simvastatin in humans is considered to be oxidation by CYP3A.…”

“…In addition, we have also demonstrated that liver injury is induced in the SDT fatty rats using allyl alcohol and carbamazepine, both of which are detoxified by glutathione conjugation in the liver (Takahashi et al, 2019a(Takahashi et al, , 2019b. These results indicate that the potential risk of chemical or drug induced liver injury is higher in diabetic patients than in healthy humans (Takahashi et al, 2019a(Takahashi et al, , 2019b. This is because statins are frequently used in patients with T2DM to treat hyperlipidemia and prevent cardiovascular events (Tolman et al, 2007).…”

“…Many nonclinical studies have been conducted with diabetes model animals in order to estimate the risk of DILI in diabetic patients (Wang et al, 2007). In our recent studies, we have demonstrated that the Spontaneously Diabetic Torii-Lepr fa (SDT fatty) rats have lower levels of hepatic reduced-form (GSH) and oxidized-form (GSSG) glutathione when compared with Sprague-Dawley (SD) rats, and the profiles of glucose metabolism, hepatic function tests and glutathione synthesis in the SDT fatty rats were like those in patients with type 2 diabetes (T2DM) (Takahashi et al, 2019a(Takahashi et al, , 2019b. In addition, we have also demonstrated that liver injury is induced in the SDT fatty rats using allyl alcohol and carbamazepine, both of which are detoxified by glutathione conjugation in the liver (Takahashi et al, 2019a(Takahashi et al, , 2019b.…”

“…In our recent studies, we have demonstrated that the Spontaneously Diabetic Torii-Lepr fa (SDT fatty) rats have lower levels of hepatic reduced-form (GSH) and oxidized-form (GSSG) glutathione when compared with Sprague-Dawley (SD) rats, and the profiles of glucose metabolism, hepatic function tests and glutathione synthesis in the SDT fatty rats were like those in patients with type 2 diabetes (T2DM) (Takahashi et al, 2019a(Takahashi et al, , 2019b. In addition, we have also demonstrated that liver injury is induced in the SDT fatty rats using allyl alcohol and carbamazepine, both of which are detoxified by glutathione conjugation in the liver (Takahashi et al, 2019a(Takahashi et al, , 2019b. These results indicate that the potential risk of chemical or drug induced liver injury is higher in diabetic patients than in healthy humans (Takahashi et al, 2019a(Takahashi et al, , 2019b.…”