Triheptanoin alleviates chlorpromazine toxicity via indirect succinic acid replenishment
10.3867/j.issn.1000-3002.2025.08197
- VernacularTitle:三庚酸甘油酯通过间接补给琥珀酸缓解氯丙嗪中毒
- Author:
Rui BAI
1
;
Wenmeng XIE
;
Chunling MA
;
Qi LOU
;
Di WEN
Author Information
1. 江苏大学附属医院病理科,江苏镇江 212000
- Publication Type:Journal Article
- Keywords:
triheptanoin;
chlorpromazine;
toxicity;
acetylcarnitine;
propionylcarnitine;
succinic acid
- From:
Chinese Journal of Pharmacology and Toxicology
2025;39(9):673-680
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE To screen endogenous differential metabolites in mice that die from chlor-promazine(CPZ)poisoning and investigate the detoxification mechanism of triheptanoin(TriHep)against CPZ-induced lethality.METHODS Mice were randomly divided into the following groups(half male and half female):normal control,CPZ 2.5LD50,CPZ LD50 intoxication(CPZI),CPZ LD50 death(CPZD),TriHep-control,and TriHep-intervention(TriHep+CPZ LD50).The CPZ 2.5LD50,CPZI and CPZD groups were intragastrically given a corresponding dose of CPZ,respectively.The TriHep-control group and the TriHep-intervention group were intragastrically given saline and CPZ LD50 respectively before being intragastrically given TriHep(3 μL·g-1)10 min later.Plasma samples from the CPZ 2.5LD50 group and normal control group were analyzed using liquid chromatography-tandem mass spectrometry(LC-MS/MS)for metabolite identification and quantification.MetaboAnalyst 5.0 was employed to perform principal component analysis(PCA),orthogonal partial least squares-discriminant analysis(OPLS-DA),and metabolic pathway analysis to screen and identify differential metabolites.More comparisons were made of the levels of differential metabolites in plasma between the normal control,CPZI,CPZD,TriHep-intervention,and TriHep-control groups.RESULTS In the PCA score plot,metabolomic samples from the CPZ 2.5LD50 group and normal control group showed clear separation,indicating distinct clus-tering patterns.Primary screening under three conditions,including P＜0.05,variable importance in projec-tion(VIP)score≥ 1 and fold change(FC)≥1.5 or ≤0.67 for a comparison of CPZ 2.5LD50 group with normal control group 28 metabolites were identified.Following quantitative enrichment and structural identifica-tion,three significantly differential metabolites were confirmed:acetylcarnitine,propionylcarnitine,and succinic acid.Compared with the normal control group,both CPZI and CPZD groups showed signifi-cantly decreased plasma levels of acetylcarnitine and propionylcarnitine,while the succinic acid content was markedly increased in the CPZD group.In the TriHep control group,levels of acetylcarnitine and succinic acid were significantly elevated,with no significant change in propionylcarnitine levels.Com-pared with the CPZI group,the CPZD group showed a significant increase in plasma succinic acid levels,but no significant change was observed in the acetylcarnitine content.The TriHep-intervention group demonstrated metabolite profiles(all the three differential metabolites)similar to those in the CPZI group,with significantly reduced propionylcarnitine and succinic acid concentrations compared to the CPZD group.CONCLUSION In the early stage of CPZ intoxication,TriHep can alleviate CPZ poisoning via acetylcarnitine,which can stabilize the level of succinic acid in plasma via indirect succinic acid replenishment.
