Griseofulvin: An Updated Overview of Old and Current Knowledge

Abstract

Griseofulvin is an antifungal polyketide metabolite produced mainly by ascomycetes. Since it was commercially introduced in 1959, griseofulvin has been used in treating dermatophyte infections. This fungistatic has gained increasing interest for multifunctional applications in the last decades due to its potential to disrupt mitosis and cell division in human cancer cells and arrest hepatitis C virus replication. In addition to these inhibitory effects, we and others found griseofulvin may enhance ACE2 function, contribute to vascular vasodilation, and improve capillary blood flow. Furthermore, molecular docking analysis revealed that griseofulvin and its derivatives have good binding potential with SARS-CoV-2 main protease, RNA-dependent RNA polymerase (RdRp), and spike protein receptor-binding domain (RBD), suggesting its inhibitory effects on SARS-CoV-2 entry and viral replication. These findings imply the repurposing potentials of the FDA-approved drug griseofulvin in designing and developing novel therapeutic interventions. In this review, we have summarized the available information from its discovery to recent progress in this growing field. Additionally, explored is the possible mechanism leading to rare hepatitis induced by griseofulvin. We found that griseofulvin and its metabolites, including 6-desmethylgriseofulvin (6-DMG) and 4-desmethylgriseofulvin (4-DMG), have favorable interactions with cytokeratin intermediate filament proteins (K8 and K18), ranging from −3.34 to −5.61 kcal mol−1. Therefore, they could be responsible for liver injury and Mallory body (MB) formation in hepatocytes of human, mouse, and rat treated with griseofulvin. Moreover, the stronger binding of griseofulvin to K18 in rodents than in human may explain the observed difference in the severity of hepatitis between rodents and human.

Antifungals: From Pharmacokinetics to Clinical Practice

“…Mitotic inhibitor that binds to polymerized fungal microtubules, inhibiting de-polymerization and leading to the failure of fungal cell replication [42].…”

“…Griseofulvin binds to tubulin and inhibits the assembly of the microtubules and the formation of the mitotic spindle, acting as a fungistatic drug against the Trichophyton, Microsporum and Epidermophyton species. However, it is ineffective in treating infections associated with dimorphic fungi, yeast (Malassezia and Candida) or chromoblastomycosis [42,59,60]. Griseofulvin is absorbed from the gastrointestinal tract and reaches the keratinized structures of the skin, justifying its success in treating dermatophytosis and onychomycosis.…”

“…Griseofulvin is absorbed from the gastrointestinal tract and reaches the keratinized structures of the skin, justifying its success in treating dermatophytosis and onychomycosis. The biological half-life of griseofulvin is 9 to 24 h in the blood and it is excreted in urine and feces after being metabolized by the liver microsomal enzyme system [42]. As for adverse effects, nausea, vomiting and diarrhea are the most frequently reported, but photosensitivity, petechiae, pruritus and urticaria have also been reported.…”

“…In addition, griseofulvin should not be used in patients with porphyria, as it decreases the bioavailability of warfarin, resulting in a decreased anticoagulant effect, and it also causes disulfiram-like reactions with ethanol. Considering the adverse effects and the hazardous drug-drug interactions, the use of griseofulvin is in most cases replaced by terbinafine and azoles [42,60].…”

Griseofulvin‐Induced Red and Hot Ears

“…It inhibits microtubule assembly, affects the formation of the mitotic spindle, and finally inhibits mitosis in dermatophytes 2 . Griseofulvin is mainly used for dermatophytes; however, other uses include anti‐inflammatory, cardiovascular, antitumor, and antiviral activity 3 . It has mainly gastrointestinal side effects, but other adverse effects can also be noticed, such as photosensitivity, urticaria, and petechia 4 …”