Natural compounds show promise in modulating heme breakdown, offering new therapeutic avenues

By Dr. Priyom Bose, Ph.D.Jan 3 2024Reviewed by Benedette Cuffari, M.Sc.

The process of heme breakdown by heme oxygenase (HMOX) yields bilirubin (BR) and biliverdin (BV) as by-products. Yellow players (YP) are enzymes involved in the production of BR and BV. YP, along with BR and BV, are considered endogenous modulators of human health and, as a result, are widely studied for their potential role in the development of novel therapeutics.

A recent Biomolecules study discusses the efficacy of natural compounds targeting YP.

Study: Role of Natural Compounds Modulating Heme Catabolic Pathway in Gut, Liver, Cardiovascular, and Brain Diseases. Image Credit: cones / Shutterstock.com

Natural compounds affecting bilirubin and its enzymes

Treatment with silymarin, a seed extract of milk thistle, and flavonolignans results in a slight elevation of total serum bilirubin (TSB) concentrations. Furthermore, flavonoids help treat neurodegenerative diseases and are promising chemoadjuvants. 

Fisetin, for example, has provided promising effects in a model of amyotrophic lateral sclerosis. Luteolin, which augments HMOX1 expression, is also considered a phototherapeutic agent for Parkinson’s Disease (PD) due to its anti-inflammatory and antioxidant properties.  

Curcumin, which originates from Curcuma longa, is an important polyphenolic compound that induces HMOX1. Many studies investigating the prevention of neurodegeneration and neurotoxicity have explored the use of curcumin as a nutraceutical. 

Astragaloside IV (AST), an active ingredient of Astragalus membranaceus var. mongholicus, promoted neuroprotection in rats with ischemic stroke. In Alzheimer’s disease (AD) patients, oxidative stress could be reduced by the consumption of vitamins C and E for one month. There is also emerging evidence that vitamin D deficiency can lead to impaired brain processes, such as cognition, and increase the risk of AD.

Other natural compounds that affect BR and its metabolic enzymes include green tea (leaf of Camellia sinensis), madecassoside (from Centella asiatica), S-Allyl Cysteine (from the garlic bulb Allium sativum), 20C (from Gastrodia elata), and Achyranthes bidentata from the Amaranthaceae family.

Natural compounds that copy products of the heme catabolic pathway

Phycocyanin, phycocyanobilin (PCB), and tetrapyrroles from Spirulina platensis are examples of natural compounds that mimic products of the heme catabolic pathway.

Spirulina (Arthrospira) platensis is rich in carotenoids, proteins, beneficial fatty acids, vitamin B complex, vitamin E, and many minerals, including zinc, copper, iron, manganese, magnesium, and selenium. Spirulina is also a rich source of potent antioxidants and has been shown to have anti-atherosclerotic and anti-cancer properties.

Due to their antioxidant properties, phycocyanin and PCB are novel and viable therapeutic options for the prevention of diabetic nephropathy. Research on male albino rats treated with streptozotocin has highlighted the antidiabetic effects of PCB, phycocyanin, and S. platensis.

Chinese medicine has used artificial bezoar for centuries in treating human diseases. To this end, pulverized bovine gallstones with at least 25% BR by weight are used.

Several studies have similarly confirmed the neuroprotective effects of artificial bezoar. For example, the remarkable reduction of ischemic damage to the brain was noted when pre-treated with An-GongNiu-Huang Wan, a Chinese medicine formulation containing bovine gallstones.

Chlorophyll is present in green leafy vegetables and is associated with protection against cancer and other neurodegenerative diseases. Recent studies have documented the antioxidant and antiproliferative effects of chlorophyll, including pheophytin a, chlorophyll a/b, and chlorophyllin.

Natural compounds that target the heme catabolic pathway

Targeting specific parts of the heme catabolic pathway is a key way to augment BR levels in tissues. Modulation of HMOX1 can be achieved through various compounds, including flavonoids, curcuminoids, caffeic acid, resveratrol, and genistein, thus demonstrating their potential role in the treatment and prevention of many autoimmune and neurodegenerative diseases.

BR-reducing bacteria in the gut lumen can alter BR levels by impacting the enterosystemic and enterohepatic circulation of BR. However, no data on potential modulation of the gut microbiome metabolizing BR are currently available.

Conclusions 

HMOX and its metabolic checkpoints can be modulated, which makes this system a viable target to combat various diseases while minimally altering diet patterns. Nevertheless, more research is needed to identify key natural food products and other compounds that can target this pathway without causing any unwanted effects.