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The human liver: not always doing the job right?

(08.01.2010)


Background:

The liver is the central organ for the metabolism. It has a wide range of functions including detoxification. The liver breaks down or modifies toxic substances preparing them for enhanced excretion.
However sometimes, the created metabolites are even more toxic than their precursors, leading to toxication. Scientists from  the University of Duisburg-Essen have studied such a case.  


Fig.: upper abdomen organs




The new study:

Bismuth is generally regarded as one of the less toxic heavy metals. It can be found in lipsticks, body powder, soothing creams and in  stomach-upset medicines.

"Inorganic bismuth compounds are used for the treatment of gastritis and ulcer or have been used in the past in Germany but are still in use in the USA" explains Markus Hollmann.

Hollmann's experiments however now demonstrate that bismuth compounds often regarded as harmless must be seen in a new light. He incubated liver (HepG2) cells with colloidal bismuth subcitrate, bismuth cysteine and bismuth gluthathione, respectively for a period of 24h. After that, the bismuth compounds produced by the liver cells were analyzed by GC/EI-MS and GC-ICP-MS using ethylation and cryofocusing of the derivates.  

The experiment clearly indicated that the liver cells metabolized the colloidal bismuth subcitrate and the bismuth cysteine into lipophilic organic bismuth compounds. Such methylation however has some negative side effects, explaiins Hollmann:

"Organic bismuth compounds are more lipophile than inorganic bismuth compounds and therefore can pass such barriers as the blood-brain barrier, reaching zones of the brain that normally cannot be reached by the inorganic compounds."

The penetration of bismuth into the brain must be regarded as dangerous. Earlier experiments have shown that organic bismuth compounds are highly toxic, damaging the brain, leading to epileptic attacks and are fatal at higher concentrations. Toxicologists assume that the compounds found in these experiments are also toxic. While the liver cells only metabolized a small part of the inorganic bismuth, such cannot be used to sound all-clear.

"we have observed transfer rates of 2-3 %, that means that some few milligrams would be metabolized when using normal dosage of the  anti-ulcer medicine. However, it is the dose that makes the toxin"

Obviously it is not yet known whether the liver cells in the human body will behave as those in the in vitro experiment.

"However the liver cells used in our experiment are pretty close to those of a living organism, having very similar functionality and therfore can be ragarded as a better model for the human body as compared to the mouse or rat."

The scientist assumes, that bismuth containing medicine might be dangerous if used in high dosage, Up to now, such medicine is still in use in the USA and many other comtries as a remedy for ulcer. Whether even the bismuth used in cosmetics might be dangerous is related to its uptake.

The next step in this ongoing research is the identification of the metabolites in human blood. Only after knowing the bismuth species present in the blood stream can the real toxicity be evaluated.


The original  study

Markus Hollmann, Jens Boertz, Elke Dopp, Joerg Hippler, Alfred Vitalis Hirner, Parallel on-line detection of a methylbismuth species by hyphenated GC/EI-MS/ICP-MS technique as evidence for bismuth methylation by human hepatic cells, Matallomics, 2 (2010) 52-56. DOI:  10.1039/b911945k



Related Studies

Jens Boertz, Louise Michele Hartmann, Margareta Sulkowski, Joerg Hippler, Frank Mosel, Roland Arturo Diaz-Bone, Klaus Michalke, Albert Wolfgang Rettenmeier, Alfred Vitalis Hirner, Determination of Trimethylbismuth in the Human Body after Ingestion of Colloidal Bismuth Subcitrate, Drug Metab. Dispos., 37/2 (2009) 352-358. doi: 10.1124/dmd.107.020313

U. von Recklinghausen, L. M. Hartmann, S. Rabieh, J. Hippler, A. V. Hirner, A. W. Rettenmeier, E. Dopp, Methylated Bismuth, but Not Bismuth Citrate or Bismuth Glutathione, Induces Cyto- and Genotoxic Effects in Human Cells in Vitro, Chem. Res. Toxicol., 21/6 (2008) 1219–1228. DOI: 10.1021/tx700304e

Klaus Michalke, Annette Schmidt, Britta Huber, Jörg Meyer, Margareta Sulkowski, Alfred V. Hirner, Jens Boertz, Frank Mosel, Philip Dammann, Gero Hilken, Hans J. Hedrich, Martina Dorsch, Albert W. Rettenmeier, Reinhard Hensel, Role of Intestinal Microbiota in Transformation of Bismuth and Other Metals and Metalloids into Volatile Methyl and Hydride Derivatives in Humans and Mice, Applied and Environmental Microbiology, 74/10 (2008) 3069-3075. doi:10.1128/AEM.02933-07

G. G. Briand, N. Burford, M. D. Eelman, N. Aumeerally, L. Chen, T. S. Cameron and K. N. Robertson, Identification, Isolation, and Characterization of Cysteinate and Thiolactate Complexes of Bismuth, Inorg. Chem., 43 (2004) 6495–6500. DOI: 10.1021/ic049594n

N. Burford, M. D. Eelman, D. E. Mahony and M. Morash, Definitive identification of cysteine and glutathione complexes of bismuth by mass spectrometry: assessing the biochemical fate of bismuth pharmaceutical agents, Chem. Commun., 2003, 146–147. DOI: 10.1039/b210570e.

Klaus Michalke, Jörg Meyer, Alfred V. Hirner, Reinhard Hensel, Biomethylation of bismuth by the methanogen Methanobacterium formicicum, Appl. Organomet. Chem., 16/4 (2002) 221-227. DOI: 10.1002/aoc.288

Glen G. Briand, Neil Burford, Bismuth Compounds and Preparations with Biological or Medical Relevance, Chem. Rev., 99/9 (1999) 2601-2658. DOI. 10.1021/cr980425s


Related EVISA Resources

EVISA Link Database: Bismuth Toxicity
EVISA Link Database: Use of bismuth compounds
EVISA brief summary: GC-ICP-MS: A very sensitive hyphenated system for speciation analysis
EVISA Journal Database: Metallomics



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