Safety Profile of Nutraceuticals Rich in Coumarins: An Update.

Simona Codruta Heghes,Oliviu Vostinaru,Cristina Mogosan,Lorena Filip,Doina Miere,Cristina Adela Iuga

doi:10.3389/fphar.2022.803338

Simona Codruta Heghes, Oliviu Vostinaru + Show 4 more

Open Access

https://doi.org/10.3389/fphar.2022.803338

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Abstract

Coumarins are a family of benzopyrones largely distributed in the natural kingdom, being present in the seeds, fruits, flowers, or roots of various plant species. Natural coumarin compounds are found in significant concentrations in some herbs or spices used as nutraceuticals, but they are also present in cosmetics or household products, due to their pleasant odor. Therefore, an accidental exposure to high doses of coumarins, could lead to the development of harmful effects in some patients. This review summarizes the latest published data from preclinical and clinical studies with natural coumarins, focused on the investigation of general and specific toxicity, with the aim of a better understanding of the safety profile of these valuable compounds. Regulatory aspects concerning the use of natural coumarins in several world regions are also reviewed.

Highlights

Nutraceuticals are bioactive substances which have become increasingly popular in the last 2 decades being used worldwide for health promotion and the prevention of various diseases
Oral LD50 of 196–780 mg/kg with signs of liver toxicity Signs of liver toxicity after 13 weeks of oral administration of doses over 50 mg/kg Intraperitoneal LD50 of 710 mg/kg Low toxicity with oral LD50 over 2000 mg/kg No mortality or signs of toxicity after oral administration of 125–2000 mg/kg Vacuolar degeneration and necrosis of hepatocytes after oral administration of 0.75% coumarin Cholestatic liver injuries in rats only after oral administration of 80 mg/kg Under 1% incidence of hepatotoxicity in patients after oral administration of 400 mg coumarin for 14 months Hepatotoxicity with abdominal pain and liver enzymes elevation in a 73-year-old patient Photoallergic reaction to furanocoumarins confirmed by histopathological test Contact stomatitis cause by cinnamon flavored chewing-gum
The results showed that cinnamon was able to inhibit CYP3A4 enzyme activity, increasing AUC of pioglitazone which is metabolized by the same isoform

Summary

Introduction

Nutraceuticals are bioactive substances which have become increasingly popular in the last 2 decades being used worldwide for health promotion and the prevention of various diseases. They are represented by numerous phytochemicals and fatty acids, amino acids or probiotics/prebiotics and may be responsible for a variety of biological effects (Nahar et al, 2021). Many natural coumarins have been successfully tested for an array of pharmacological properties like anti-inflammatory, antioxidant, antimicrobial, antidepressant, neuroprotective or antitumoral effects (Srikrishna et al, 2018). Several natural coumarins have served as scaffolds for the development of authorized drugs like warfarin, other drug candidates with different pharmacological properties being constantly developed (Bansal et al, 2013)

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