Pyrrolizidine
alkaloids (PAs) are the most common toxins
of plant
origin, and it is evident that PAs pollute soil, water, nearby plants,
and derived foods. Cases of human poisoning due to ingestion of PA-contaminated
foods have been reported in several countries. Monocrotaline (MCT)
is a pyrrolizidine alkaloid from the plants of Crotalaria genus that causes hepatic and cardiopulmonary toxicities, and the
exhibition of the toxicities requires the metabolic activation by
CYP3A4 to form electrophilic dehydro-monocrotaline (DHM). The present
study demonstrated that myeloperoxidase (MPO) also participated in
the bioactivation of MCT. N-Chloromonocrotaline was
detected in both HClO/MCT incubations and MPO/H2O2/MgCl2/MCT incubations. DHM-derived N-acetylcysteine (NAC) conjugates were detected in the above incubations
fortified with NAC. Lipopolysaccharide-induced inflammation in mice
resulted in an elevated level of hepatic MPO activity, increased metabolic
activation of MCT, and intensified elevation of serum ALT and AST
activity induced by MCT. MPO inhibitor 4-aminobenzoic acid hydrazide
was found to reverse these alterations. Mpo-KO mice
were resistant to the observed potentiating effect of inflammation
on MCT-induced liver injury. In conclusion, inflammation intensified
MCT-induced liver injury. MPO participated in the observed potentiating
effect of inflammation on the hepatotoxicity induced by MCT.
Background: Aidi Injection (ADI), a Chinese herbal preparation with anti-cancer activity, is used for the treatment of hepatocellular carcinoma (HCC). Several clinical studies have shown that co-administration of ADI with doxorubicin (DOX) is associated with reduced toxicity of chemotherapy, enhanced clinical efficacy and improved quality of life for patients. However, limited information is available about the herb-drug interactions between ADI and DOX. The study aimed to investigate the pharmacokinetic mechanism of herb-drug interactions between ADI and DOX in a rat model of HCC.Methods: Experimental HCC was induced in rats by oral administration of diethylnitrosamine. The HCC rats were pretreated with ADI (10 mL/kg, intraperitoneal injection) for 14 consecutive days prior to administration of DOX (7 mg/kg, intravenous injection) to investigate pharmacokinetic interactions. Plasma concentrations of DOX and its major metabolite, doxorubicinol (DOXol), were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).Results: Preadministration of ADI significantly altered the pharmacokinetics of DOX in HCC rats, leading to increased plasma concentrations of both DOX and DOXol. The area under the plasma drug concentration-time curve (AUCs) of DOX and DOXol in rats pretreated with ADI were 3.79-fold and 2.92-fold higher, respectively, than those in control rats that did not receive ADI.Conclusions: Increased levels of DOX and DOXol were found in the plasma of HCC rats pretreated with ADI.
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