Substrates of Human CYP2D6
Shufeng Zhou in Cytochrome P450 2D6, 2018
A study using human liver microsomes indicated that CYP2D6 and 3A4 are able to metabolize emetine to cephaeline (both are alkaloids from ipecac) and 9-O-demethylemetine, and CYP3A4 also participated in metabolizing emetine to 10-O-demethylemetine (Asano et al. 2001). The CYP2D6 enzyme also has high affinity for toxic plant alkaloids such as lasiocarpine and monocrotaline, both pyrrolizidine alkaloids (Wolff et al. 1985, 1987). Pyrrolizidine alkaloids are found in plants growing in most environments and all parts of the world. They have long been known to be a health hazard for livestock, wildlife, and humans (Stegelmeier et al. 1999). Plants known or suspected to contain toxic alkaloids are widely used for medicinal purposes as home remedies all over the world, without systematic testing for safety (Roeder 2000). Most pyrrolizidine alkaloids are hepatotoxic (Liddell 2001). The following are the major metabolic pathways of unsaturated pyrrolizidine alkaloids such as lasiocarpine in animals (Figures 3.112 and 3.113) (Cheeke 1988; Fu et al. 2004; Liddell 2001): (a) hydrolysis of the ester groups, (b) N-oxidation, and (c) dehydrogenation of the pyrrolizidine nucleus to dehydro-alkaloids (pyrrolic derivatives). Routes a and b are believed to be detoxification mechanisms, while route c leads to toxic metabolites capable of binding DNA and proteins and appears to be the major activation mechanism (Fu et al. 2004; Zhou et al. 2007). Both lasiocarpine and monocrotaline are procar-cinogens that are bioactivated by P450s to carcinogens (Xia et al. 2006).
Alternative Medicines Based on Aboriginal Traditional Knowledge and Culture
Yasmina Sultanbawa, Fazal Sultanbawa in Australian Native Plants, 2017
The sap from bruised leaves of Crotalaria cunninghamii was reportedly poured into the ears to relieve earache (Lassak and McCarthy, 2001; Reid and Betts, 1979). It is thought that alkaloids are the compounds most likely to account for the bioactivity of this plant, but, compared to other Crotalaria species at least, the alkaloid content is low (Fletcher et al., 2008). However, the pyrrolizidine alkaloid retusamine is the main component in extracts of new growth and flowering tops (Fletcher et al., 2008), and monocrotaline is a major constituent of the seeds of most Crotalaria species (Pilbeam et al., 1983). Pyrrolizidine alkaloids such as these cause liver and lung damage and so are toxic if ingested too frequently (Roeder and Wiedenfeld, 2009). Aboriginal people probably understood this very well as, from all accounts, they only used Crotalaria species in external applications (Lassak and McCarthy, 2001; Smith, 1991).
Nutraceuticals Impacting Uterine Growth, Gestational Age and Mortality Rate
Priyanka Bhatt, Maryam Sadat Miraghajani, Sarvadaman Pathak, Yashwant Pathak in Nutraceuticals for Prenatal, Maternal and Offspring’s Nutritional Health, 2019
Later, through research, it was discovered that the leaves of this plant contained a low toxicity alkaloid called pyrrolizidine (USDA NRCS). Pyrrolizidine alkaloids (PA) are plant toxins, which cause human as well as plant diseases. During the metabolism process of this plant, the liver converts the alkaloids into highly reactive electrophiles that react with the macromolecules to form an adduct, further resulting in either acute or chronic toxicity. PAs are also known to act as teratogens and as abortifacients (Prakash et al. 1999). All herbal abortifacients are to be avoided during pregnancy since the side effects can be harmful to the pregnant mother.
Diurnal hepatic CYP3A11 contributes to chronotoxicity of the pyrrolizidine alkaloid retrorsine in mice
Published in Xenobiotica, 2021
Li Guo, Li Zhang, Haiman Xu, Pei Yu, Zhigang Wang, Danyi Lu, Min Chen, Baojian Wu
Pyrrolizidine alkaloids are a class of naturally occurring phytotoxins distributed in thousands of plants [e.g. Senecio, Ligularia, Eupatorium (Asteraceae), Crotalaria (Fabaceae), Heliotropium, and Cynoglossum (Boraginaceae) species] (Roeder 2000). Human and livestock poisoning events for pyrrolizidine alkaloid-containing plants have been reported in many countries such as Russia, Indian, Afghanistan, Jamaican, South African, Australia and America (Fu et al. 2004; Liu et al. 2010; Liang et al. 2011). Pyrrolizidine alkaloids cause toxicities to various tissues and organs including the liver, brain, lung and embryo (Tu et al. 1988; Buhler et al. 1991; Taylor et al. 1997; Roeder 2000; Fu et al. 2004). There are mainly two types of toxic pyrrolizidine alkaloids, namely, retronecine-type and otonecine-type. Retrorsine (RTS) is one of the most hepatotoxic retronecine-type alkaloids and is found mainly in Senecio genus (Buhler et al. 1991; Fu et al. 2004). RTS is a 12-membered macrocyclic diester alkaloid with an α, β-unsaturated double bond linked to the ester group at the C-7 position of the necine base (see Figure 1 for chemical structure) (Dai et al. 2010). Therefore, new strategies (i.e. the chronotherapeutic approach) are needed to reduce the toxicity of pyrrolizidine alkaloids (e.g. RTS).
Differential effect of herbal tea extracts on free fatty acids-, ethanol- and acetaminophen-induced hepatotoxicity in FL83B hepatocytes
Published in Drug and Chemical Toxicology, 2022
Guan-Wen Chen, Tai-Yuan Chen, Pei-Ming Yang
It is well recognized that drug and/or medicine intakes together with concomitant alcohol consumption may cause toxic interactions or liver damage due to alcohol-induced pharmacokinetic changes in the hepatic drug metabolism pathways catalyzed by the various cytochrome P450 enzymes (Weathermon and Crabb 1999, Tanaka et al.2007). Our results indicated that all herbal tea extracts enhanced the alcohol-induced hepatotoxicity, suggesting that alcohol may also interact with the components of herbal tea extracts. It has been reported that pyrrolizidine alkaloids purified from herbal remedies can enhance alcohol-induced hepatotoxicity in vitro in normal human hepatocytes by inducing the inflammatory cytokines and enhancing the apoptotic effects of ethanol (Neuman et al.2017). Pyrrolizidine alkaloids are frequently found in herbal plants and they are toxic to animals and human (Smith and Culvenor 1981, Lindigkeit et al.1997, Li et al.2011). Metabolic activation of pyrrolizidine alkaloids by cytochrome P450 enzymes is required for generating reactive pyrrolic metabolites that damage cellular proteins and DNA. However, it is uncertain whether the herbal tea extracts used in this study contained pyrrolizidine alkaloids because no obvious hepatotoxicity was observed. Because the enhancement of ethanol-induced hepatotoxicity was a common effect of these herbal tea extracts, further characterization of their phytochemical constitution in the future will facilitate our understanding about the herb-alcohol interactions.
Antimicrobial activity of flavonoids glycosides and pyrrolizidine alkaloids from propolis of Scaptotrigona aff. postica
Published in Toxin Reviews, 2023
T. M. Cantero, P. I. Silva Junior, G. Negri, R. M. Nascimento, R. Z. Mendonça
Propolis from Scaptotrigona aff. postica (Apidae, Meliponini) possess potential for chemical and biological exploration. Samples of propolis of S. postica were collected monthly from an apiary located in Barra do Corda (state of Maranhão, northeast Brazil). Extracts of the twelve samples were obtained with 80% ethanol. Constituents of the samples were characterized by HPLC-PAD-ESI-MS/MS analysis and were found 100 compounds. Pyrrolizidine alkaloids and flavones-C-glycosides was detected only in samples collected in October, November and December (Negri et al. 2022). In the present study, preparative liquid chromatography in reversed-phase column allowed the separation of fractions 40AEP and 40MEP, rich in alkaloids and flavonoids. Alkaloids are distributed in many classes including pyrrolizidines, pyrrolidines, quinolizidines, indoles, tropanes, piperidines, purines, imidazoles, and isoquinolines (Moreira et al. 2018). Pyrrolizidine alkaloids are produced as defense chemicals against herbivores and occur in several species of plants relevant for human and animal nutrition, such as, in the angiosperm family of Boraginaceae (all genera), Asteraceae (tribes Senecioneae and Eupatorieae) and Fabaceae (genus Crotalaria) families (Moreira et al. 2018, Tasca et al. 2018, Schramm et al. 2019, Mädge et al. 2020).
Related Knowledge Centers
- Alkaloid
- Borage
- Fabaceae
- Hepatotoxicity
- Liver
- Liver Cancer
- Carcinogenesis
- Amine Oxide
- Hepatic Veno-Occlusive Disease
- Pyrrolizidine Alkaloidosis