Benzimidazoles- Fungi and Helminths Beware!

Benzimidazoles what are they?

Benomyl, the most common of the Benzimidazoles. source: https://en.wikipedia.org/wiki/Benomyl

Benzimidazoles are a class of fungicides which was invented by DuPont industries as a methyl ester of [1-(butylcarbamoyl)-1H-benzimidazol-2-yl]carbamic acid. (1)

Production of Benzimidazoles are through a condesation reaction between phenylenediamine and formic acid as seen below in the equation below:(2)

C6H4(NH2)2 + HC(OCH3)3 → C6H4N(NH)CH + 3 CH3OH

Benzimidazoles additionally have anti-helminthic effects on Nematodes, lungworms, some cestodies, some trematodes and adult flukes.(3)

The typical chemical conformation of benzimidazole- a imidazole and benzene bicyclic compound. source: https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+2797

https://www.google.com/search?biw=738&bih=657&tbm=isch&sa=1&ei=BHxAXdLmIZjPtQaW07XoBA&q=benzimidazole+product&oq=benzimidazole+product&gs_l=img.3…1060.4004..4119…0.0..0.235.947.5j2j1……0….1..gws-wiz-img…….0j0i8i30j0i24.QlI-Q1UndrI&ved=0ahUKEwjS-PGik93jAhWYZ80KHZZpDU0Q4dUDCAY&uact=5#imgrc=MOu66yWBhVAr0M:

Biotransformative effects:

Biotransformation studies have been have been carried out in various animal models ranging from rodents to ruminants to humans.

When in regards to the Benzimidazole, Albendazole, typically this process occurs as a 2 step process yielding albendazole sulphoxide and albendazole sulphone. albendazole sulphoxide is mediated by CYP3A and Flavine monooxygenases while albendazole sulphone is mediated through CYP1A.

When Fenbendazole is the Benzimidazole being used, typically biotransformation occurs into sulphoxide. The exact enzymes causing this are not definitively known but likely are due to CYP1A1/2. (4)

https://www.google.com/search?q=benzimidazole+biotransformation&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiEifPtk93jAhVSHqwKHcgND0IQ_AUIESgB&biw=746&bih=657&dpr=1.8#imgrc=-QZcK7LI1fjDHM:

 

Toxicokinetics of Benzimidazoles:

Benzimidazole will cause toxicokinetic effects through affecting metabolic pathways. Research into the specific pathways involved is sparse, but some definitive toxicokinetics have been shown.

Oral injestion tends to be the most rapid route of absorption in the body and the Benzimidazoles tend to be more fat soluble than water soluble. Excretion is through in the urine as 5-hydroxythiabendazole.(11)

Mechanism of Action of Benzimidazoles:

Although the exact mechanism of action for Benzimidazoles are not known there are a few clear effects.

On fungi, growth is stunted through inhibiting microtubule formation (5).

In parasite nematodes, several different effects have been found to be associated with Benzimidazoles including: fumarate reductase inhibition, energy production inhibition, glucose transport and uptake inhibition, as well as, microtubule degeneration and dissolution.(6)(7)

Carcinogenicity and Teratogenicity of Benzimidazoles:

Typically benzimidazoles have been shown to cause liver tumors in rats. Benzimidazoles have not been shown to cause carcinogenesis normally in other species. (8)

Teratogenesis is common in benzimidazoles but is dependent on the dose and species. In cattle, pigs and horses this will present as skeletal defects in the animals.(9)

In humans teratogenesis has been reported to present as anopthalmia when the benzimidazole, benomyl is given. (5) Anopthalmia is the abscence of the globe and ocular tissue as seen below:

source: https://www.cdc.gov/ncbddd/birthdefects/anophthalmia-microphthalmia.html

When the law gets involved with Benzimidazoles Exposures:

The most historically relevant exposure to benzimidazoles was in Miami in 1996. A child was born with anopthalmia due to the mother’s occupation as a gardener. A law suit ensued with a final verdict of 4 million dollars!

Target Organs of Benzimidazoles:

Studies have shown that benzimidazole will affect the testes, Gastrointestinal tract, bone marrow and liver if exposure is chronic. (10) Additionally, benomyl can cause a contact dermititis. (5)

https://www.google.com/search?q=contact+dermatitis&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiPhNCElN3jAhXDmq0KHb3YCVkQ_AUIESgB&biw=555&bih=657&dpr=1.8

Signs and Symptoms of Benzimidazoles:

Inhalation and dermal contact are the most common routes of exposure of benzimidazoles which can lead to toxicity. Signs can present nonspecifically as weakness, nausea, dizziness, headaches, and irritation to mucosa, skin and the lungs. When inhaled a hypersensitivity can occur leading to bronchospasm and wheezing. Dermal exposure can lead to hypersensitivity dermatitis. (11)

Treatment for Benzimidazoles?

As with any toxicity case which presents 6 steps are traditionally taken for management:(12)

  1. Stabilizing the patient to ensure open airways, breathing and proficient circulation.
  2. Evaluating how stabile the patient is through complete blood counts, blood gas and other assays.
  3. Prevention of further contamination through removing clothing which has been exposed.
  4. Enhancement of elimination through the use of activated charchoal. This has been found to be especially useful with benzimidazoles toxicity.
  5. There is no antidote to benzimidazoles poisioning.
  6. Supportive care to the patient through bronchodilators or mechanical ventilation.

Biomarkers for Benzimidazoles?

There are currently no biomarkers for benzimidazole. Scientists seem to have no interest in making a biomarker for benzimidazoles in the future.

BUT! Benzimidazoles has been recently found to be a useful stain for endoplasmic reticulum and golgi apparatus! Follow the link below for a video of the fluorescence in a live cell! (13)

https://figshare.com/articles/Video_1_New_Properties_of_a_Bioinspired_Pyridine_Benzimidazole_Compound_as_a_Novel_Differential_Staining_Agent_for_Endoplasmic_Reticulum_and_Golgi_Apparatus_in_Fluorescence_Live_Cell_Imaging_AVI/7021787/1

Additionally, specific benzimidazoles have been shown to be preliminarily useful as anti-inflammatories! see video below for the full details: (14)

 

 

Citations:

(1) ChEBI. 2015. https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:3015

(2) E. C. Wagner and W. H. Millett (1943). “Benzimidazole”Organic SynthesesCollective Volume2, p. 65.

(3) Bowman, Dwight D. Georgis’ Parasitology for Veterinarians. Philadelphia :W.B. Saunders Co., 1999.

(4) Velik, J, et al. “Benzimidazole Drugs and Modulation of Biotransformation Enzymes.” Research in Veterinary Science, W.B. Saunders, 24 Sept. 2003, www.sciencedirect.com/science/article/pii/S0034528803001498.

(5) Curtis D. Klaassen. Casarett And Doull’s Toxicology : the Basic Science of Poisons. New York :McGraw-Hill Education, 2013.

(6) L.C. Davidse, Ann. Rev. Phytopathol., 24 (1986), p. 43

(7) J.C. Havercroft, R.A. Quinlan, K. Gull. J. Cell. Sci., 49 (1981), p. 195

(8) Onodera, H, et al. “Intensity of Liver Tumor Promotion Effects in Rats given Repeated Oral Administrations of Benzimidazole Compounds.” Eisei Shikenjo Hokoku. Bulletin of National Institute of Hygienic Sciences, U.S. National Library of Medicine, 1996, www.ncbi.nlm.nih.gov/pubmed/9037860.
(9)Maddison, Jill E., et al. Small Animal Clinical Pharmacology. Saunders Elsevier, 2009.
(10) Gupta, Ramesh Chandra. Veterinary Toxicology Basic and Clinical Principles. Elsevier, 2007.
(11)“Benzimidazole.” U.S. National Library of Medicine, National Institutes of Health, 2003, toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs%2Bhsdb%3A%40term%2B%40DOCNO%2B2797.
(12)Plahovinsak, J. “PHRM7588: Toxic Substances.” Carmen.com, 2019.
(13) Llancalahuen, et al. “Video_1_New Properties of a Bioinspired Pyridine Benzimidazole Compound as a Novel Differential Staining Agent for Endoplasmic Reticulum and Golgi Apparatus in Fluorescence Live Cell Imaging.AVI.” Figshare, Frontiers, 29 Aug. 2018, figshare.com/articles/Video_1_New_Properties_of_a_Bioinspired_Pyridine_Benzimidazole_Compound_as_a_Novel_Differential_Staining_Agent_for_Endoplasmic_Reticulum_and_Golgi_Apparatus_in_Fluorescence_Live_Cell_Imaging_AVI/7021787/1.
(14)Press, Dove Medical. “Efficacy and Safety of Two Novel Bipyrazole Compounds – Video Abstract [ID 157955].” YouTube, YouTube, 2 Apr. 2018, www.youtube.com/watch?time_continue=166&v=WR0Cz2akaP4.

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