Abstract
Aconitum, widely used to treat rheumatoid arthritis for thousands of years, is a toxic herb that can frequently cause fatal cardiac poisoning. Aconitum toxicity could be decreased by properly hydrolyzing diester-diterpene alkaloids into monoester-diterpene alkaloids. Monoester-diterpene alkaloids, including benzoylaconine (BAC), benzoylmesaconine (BMA), and benzoylhypaconine (BHA), are the primary active and toxic constituents of processed Aconitum. Cytochrome P450 (CYP) enzymes protect the human body by functioning as the defense line that limits the invasion of toxicants. Our purposes were to identify the CYP metabolites of BAC, BMA, and BHA in human liver microsomes and to distinguish which isozymes are responsible for their metabolism through the use of chemical inhibitors, monoclonal antibodies, and cDNA-expressed CYP enzyme. High-resolution mass spectrometry was used to characterize the metabolites. A total of 7, 8, and 9 metabolites were detected for BAC, BMA, and BHA, respectively. The main metabolic pathways were demethylation, dehydrogenation, demethylation-dehydrogenation, hydroxylation and didemethylation, which produced less toxic metabolites by decomposing the group responsible for the toxicity of the parent compound. Taken together, the results of the chemical inhibitors, monoclonal antibodies, and cDNA-expressed CYP enzymes experiments demonstrated that CYP3A4 and CYP3A5 have essential functions in the metabolism of BAC, BMA, and BHA.
Highlights
Aconitum has been used as an essential drug in China and in other East Asian countries for centuries owing to its extremely excellent effect against rheumatosis and rheumatoid arthritis [1, 2]
Pooled human liver microsomes (HLMs, 20 mg/mL, including reductase), β-nicotinamide adenine dinucleotide phosphate (NADP), glucose-6-phosphate (6-P-G), and glucose6-phosphate dehydrogenase (PDH) were purchased from BD Gentest Corp. (Woburn, MA, USA). cDNA-expressed Cytochrome P450 (CYP) enzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, and 3A5), chemical inhibitors [22,23,24,25,26,27], and inhibitory monoclonal antibodies were obtained from BD Gentest Corp. (Woburn, MA, USA)
Compared with the negative control, a total of 7 BAC metabolites, 8 BMA metabolites and 9 BHA metabolites were found in the HLMs along with the NADPH-regenerating system (Figure 1)
Summary
Aconitum has been used as an essential drug in China and in other East Asian countries for centuries owing to its extremely excellent effect against rheumatosis and rheumatoid arthritis [1, 2]. It was reported that among 500 known prescriptions, the frequency of use of the Aconitum is 13.20%, ranked 9 [3]. Aconitum is a toxic herb that can cause fatal cardiac poisoning [4,5,6] and is reportedly involved in suicidal and homicidal attempts [6, 7]. Since the therapeutic dose of Aconitum is very close to its toxic dose, its poisoning incidents are not uncommon. According to the literature data, in 188 cases of patients with Aconitum, 111 patients had varying degrees of toxic reactions [3]. The toxicological mechanism of Aconitum is widely recognized to be associated with voltage-dependent Na+ channels [8]
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