Metabolic Activation of the Toxic Natural Products From Herbal and Dietary Supplements Leading to Toxicities

Abstract

Currently, herbal and dietary supplements have been widely applied to prevent and treat various diseases. However, the potential toxicities and adverse reactions of herbal and dietary supplements have been increasingly reported, and have gradually attracted widespread attention from clinical pharmacists and physicians. Metabolic activation of specific natural products from herbal and dietary supplements is mediated by hepatic cytochrome P450 or intestinal bacteria, and generates chemical reactive/toxic metabolites that bind to cellular reduced glutathione or macromolecules, and form reactive metabolites-glutathione/protein/DNA adducts, and these protein/DNA adducts can result in toxicities. The present review focuses on the relation between metabolic activation and toxicities of natural products, and provides updated, comprehensive and critical comment on the toxic mechanisms of reactive metabolites. The key inductive role of metabolic activation in toxicity is highlighted, and frequently toxic functional groups of toxic natural products were summarized. The biotransformation of drug cytochrome P450 or intestinal bacteria involved in metabolic activation were clarified, the reactive metabolites-protein adducts were selected as biomarkers for predicting toxicity. And finally, further perspectives between metabolic activation and toxicities of natural products from herbal and dietary supplements are discussed, to provide a reference for the reasonable and safe usage of herbal and dietary supplements.

Glutathione S-Transferases Mediate In Vitro and In Vivo Inactivation of Genipin: Implications for an Underlying Detoxification Mechanism

“…Normally, the formation of reactive metabolites in herbal medicines or dietary supplements is mediated by hepatic cytochrome P450 or intestinal bacteria. The reactive species formed can covalently bind to cellular macromolecules, including proteins, DNA, and lipids, subsequently triggering toxicity in various manners . The hydrolysis of GE mainly forms GP via the catalysis of intestinal microbiota .…”

Structural Elucidation of Novel Stable and Reactive Metabolites of Green Tea Catechins and Alkyl Gallates by LC-MS/MS

“…Sang et al [ 47 ] found that EGCG can also be oxidized by peroxidase and hydrogen peroxide and then react with cysteine or glutathione, however, studies involving the formation GSH adducts of green tea catechins are still limited. The formation of such adducts scavenges potentially toxic reactive metabolites and reduces their potential for binding to cellular macromolecules [ 48 , 49 ]. From the results presented here, GSH was proven to bind on EGCG and its analogs in the B-ring or D-rings ( Figure 6 ).…”

Transcriptomics and metabolomics reveal the role of CYP1A2 in psoralen/isopsoralen‐induced metabolic activation and hepatotoxicity

“…It is cautioned that potential side effects of interactions between psoralen or isopsoralen with CYP1A2 Furan-containing compounds are often suspected to bring about hepatotoxicity through the formation of reactive intermediates by metabolic activation of CYP450, which subsequently bind to intracellular GSH, DNA, proteins, etc., and induce cytotoxicity (Peterson, 2013;Wang et al, 2021). This theory has undergone some practices (Khojasteh et al, 2020;Wang et al, 2021), for example, furanoid diterpene lactones of disobulbin A, B, C, and F isolated from Dioscorea bulbifera L. were metabolized by CYP3A to cis-enedial intermediates, which were responsible for the observed hepatotoxicity (Li et al, 2016;Wu et al, 2020). In addition, the furan rings of furancontaining components such as rutaevin (Liu, Li, et al, 2020;, columbin (Pei et al, 2020), nomilin (Zhang et al, 2020), etc.…”

“…To further clarify the correlation between CYP1A2-mediated metabolism and psoralen/isopsoralen-induced hepatotoxicity, models of induction and inhibition of CYP1A2 in vitro and in vivo were constructed, and the results indicated that the hepatotoxicity of psoralen and isopsoralen was aggravated when CYP1A2 expression was induced, whereas the hepatotoxicity was attenuated when CYP1A2 was inhibited, indicating that CYP1A2 metabolism might be the key trigger for psoralen/ isopsoralen-induced hepatotoxicity. It is cautioned that potential side effects of interactions between psoralen or isopsoralen with CYP1A2 Furan-containing compounds are often suspected to bring about hepatotoxicity through the formation of reactive intermediates by metabolic activation of CYP450, which subsequently bind to intracellular GSH, DNA, proteins, etc., and induce cytotoxicity (Peterson, 2013;Wang et al, 2021). This theory has undergone some practices (Khojasteh et al, 2020;Wang et al, 2021), for example, furanoid diterpene lactones of disobulbin A, B, C, and F isolated from Dioscorea bulbifera L. were metabolized by CYP3A to cis-enedial intermediates, which were responsible for the observed hepatotoxicity (Li et al, 2016;Wu et al, 2020).…”

“…The formation of reactive metabolites catalyzed by CYP450 and subsequent oxidative stress are the common pathway for metabolism-mediated xenobiotic-induced toxicity (Jee, Sernoskie, & Uetrecht, 2021;Wang et al, 2021). The presence of high levels of reactive oxygen species could disrupt the defense system of organisms, with impairments of critical cellular components such as DNA and proteins (Deavall, Martin, Horner, & Roberts, 2012;Pereira, Nadanaciva, Oliveira, & Will, 2012).…”