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. 2024 Feb 23:15:1358262.
doi: 10.3389/fphar.2024.1358262. eCollection 2024.

Associations between one-carbon metabolism and valproic acid-induced liver dysfunction in epileptic patients

Jingwei Zhu #  1 , Zhe Wang #  1 , Xiaotong Sun #  1 , Dan Wang  2 , Xinbo Xu  1 , Liping Yang  1 , Jiangdong Du  1 , Zhimei Zhou  1 , Yanhua Qi  1 , Linfeng Ma  1
Affiliations

Associations between one-carbon metabolism and valproic acid-induced liver dysfunction in epileptic patients

Jingwei Zhu et al. Front Pharmacol. .

Abstract

Valproic acid (VPA) has been widely used as an antiepileptic drug for decades. Although VPA is effective and well-tolerated, long-term VPA treatment is usually associated with hepatotoxicity. However, the underlying mechanisms of VPA-caused hepatotoxicity remain unclear. In this study, a total of 157 pediatric patients with epilepsy were recruited and divided into normal liver function (NLF, 112 subjects) group and abnormal liver function (ABLF, 45 subjects) group. We observed that MTHFR A1298C and MTHFR C677T variants may be linked to VPA-induced liver dysfunction (p = 0.001; p = 0.023, respectively). We also found that the MTHFR A1298C polymorphism was associated with a higher serum Hcy level (p = 0.001) and a lower FA level (p = 0.001). Moreover, the serum Hcy levels was strongly correlated with the GSH and TBARS concentrations (r = -0.6065, P < 0.001; r = 0.6564, P < 0.001, respectively). Furthermore, logistic analysis indicated that MTHFR A1298C/C677T polymorphisms and increased Hcy concentrations may be risk factors for VPA-induced liver dysfunction. These results suggested that individual susceptibility to VPA-induced liver dysfunction may result from MTHFR A1298C/C677T polymorphisms and increased Hcy levels. This study may be helpful for the prevention and guidance of VPA-induced liver dysfunction.

Keywords: MTHFR A1298C; MTHFR C677T; Valproic acid; homocysteine; liver dysfunction; one-carbon metabolism; oxidative stress.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic of One-Carbon metabolism related folate cycle, methionine cycle and transsulfration pathway. MTHFR, methylene tetrahydrofolate reductase; MTR, methionine synthase; MTRR, methionine synthase reductase CBS, cystathionine beta-synthase; ROS, reactive oxygen species.
FIGURE 2
FIGURE 2
Associations between plasma VPA concentrations and OCM-related nutrition levels of all subjects (ABLF and NLF groups). Relationships between (A) plasma VPA concentrations and folate levels. (B) plasma VPA concentrations and homocysteine levels. (C) plasma VPA concentrations and Vitamin B12 levels.
FIGURE 3
FIGURE 3
Effect of genetic polymorphisms on OCM-related nutrition levels. (A) MTHFR A1298C variant and serum Hcy levels. (B) MTHFR A1298C variant and serum FA levels. (C) MTHFR A1298C variant and serum Vitamin B12 levels. (D) MTHFR C677T variant and serum Hcy levels. (E) MTHFR C677T variant and serum FA levels. (F) MTHFR C677T variant and serum Vitamin B12 levels. *p < 0.05, **p < 0.01.
FIGURE 4
FIGURE 4
Association among plasma VPA concentration, serum Hcy levels and oxidative stress parameters of all subjects (ABLF and NLF groups). Relationships between (A) plasma VPA concentrations and GSH levels. (B) plasma VPA concentrations and TBARS levels. (C) serum Hcy concentration and GSH levels. (D) serum Hcy concentration and TBARS levels.
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