Interactions between Phytochemicals from Traditional Chinese Medicines and Human Cytochrome P450 Enzymes

Abstract

Traditional Chinese medicine (TCM) formulas with fixed combinations rely on "sovereign, minister, assistant and guide" and fuzzy mathematical quantitative law, leading to greater challenges for the identification of active ingredients. Transformation and metabolic studies involving the Phase I drug-metabolizing enzyme cytochrome P450 (CYP) might potentially solve some of these challenges. The pharmacological effects can not be attributed to one active ingredient in TCMs, but integrated effects resulting from the combined actions of multiple ingredients. However, it is only after long-term administration that most ingredients exert their actions, which can result in prolonged exposure to herbs in vivo. Therefore, interactions between herbal compounds and CYPs appear to be inevitable. Yet unlike Western drugs, experimental determination of the absorption and disposition properties is not commonly carried out for TCMs. Moreover, the use of TCM as injections is an innovation aimed to improve efficiency in extensive clinical use in Mainland China. Therefore, in recent years, cases of adverse drug reactions (ADR) mainly concerning allergic reactions involving TCMs such as ShenMai injection and QingKaiLing injection have been reported, which have attracted attention with regard to the legal responsibilities for TCM approval. The lack of information on the ADME characteristics, especially the metabolic stability and interaction potential between CYPs and herbs, increases ADR occurrence due to TCMs. In this article, we review the most common herbs used in TCM prescriptions and fixed combinations of their usable frequency, and summarize the current understanding of the ability of phytochemical ingredients to act as substrates, inhibitors or inducers of human CYP enzymes, through which the key role of CYP enzymes on the herb disposition and toxicity is highlighted. The potential interaction between herbal phytochemicals and CYP enzymes dominates the target exposure, which further helps to elucidate the herbal pharmacological basis, assess the individual toxic risk of herbal remedies and gain mechanistic insight into herb-drug interactions (HDIs).

Traditional Chinese Medicine (TCM) and Herbal Hepatotoxicity: RUCAM and the Role of Novel Diagnostic Biomarkers Such as MicroRNAs

“…Therefore, these phytochemicals must undergo enzymatic degradation and disposition following intestinal resorption by processes similar to those known for synthetic drugs, involving bioactivation pathways via the cytochrome P450 (CYP) systems (Phase I), conjugation to other molecules (Phase II), and excretion and transport (Phase III) [140,192,193,194,195,196,197,198]. Examples for such metabolic steps are provided for many TCM herbs [194,195] such as Polygonum multiflorum [196], Lu Cha (green tea) [140], Shi Can (germander) [199,200,201], and PAs containing herbs [28,120,122,201]. Genetic variation may cause polymorphisms of CYP [192,193], which has recently been reported also in Chinese patients with acute liver injury by Polygonum multiflorum [196], who showed a 46.5% higher frequency of CYP1A2*1C allele as compared to 27.9% in the healthy control group.…”

“…Other molecular risk factors of liver injury relate to the extraction process used in herbal TCM manufacturing, which is conventionally based on decoction and alcohol sedimentation techniques [194]. Besides the water soluble components, many liposoluble constituents are included in the final herbal TCM preparations and require biotransformation.…”

Peony-Glycyrrhiza Decoction, an Herbal Preparation, Inhibits Clozapine Metabolism via Cytochrome P450s, but Not Flavin-Containing Monooxygenase in In Vitro Models

“…CYPs also play a critical role in the kinetic interaction between liquorice and peony and conventional drugs (Chen et al, 2002;Wang et al, 2013c;Wu et al, 2012;Zhou et al, 2003). Flavin-containing monooxygenases (FMOs) are hepatic microsomal enzymes with importance in catalyzing massive xenobiotics (Krueger et al, 2005).…”

Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A

“…Previously, our laboratory has screened the CYP3A substrates from a large number of Traditional Chinese Medicines that are classified as superior drugs (Wu et al, 2012). Fructus Schisandrae has been used for thousands of years, owing to its diverse pharmacological effects (Wei et al, 2010).…”