Improvement in dissolution of liver fibrosis in an animal model by tetrathiomolybdate.
The background for this study is that we have observed some improvement in cirrhosis in Wilson's disease patients treated with the anticopper medicine, zinc, and another anticopper drug, tetrathiomolybdate, has completely prevented hepatic fibrosis in the carbon tetrachloride mouse model. We hypothesize that in existing cirrhosis, there may be a fine balance between fibrosis formation and fibrosis dissolution, which may be pushed in the direction of dissolution by anticopper drugs. Thus, in this study, we produced hepatic fibrosis in mice by treatment with carbon tetrachloride, then gave half the fibrotic mice tetrathiomolybdate for 3 months, while the other half of the fibrotic mice received nothing for 3 months and served as controls. Tetrathiomolybdate caused a dramatic and significant reduction in fibrosis as measured by hydroxyproline (the major amino acid constituent of collagen) levels, almost back to baseline levels, compared to controls, who had only a slight and nonsignificant reduction. It is clear from this animal study that dissolution of preexisting fibrosis can be strongly catalyzed by lowering copper levels with tetrathiomolybdate. It now becomes important to evaluate whether this approach will work in the human epidemic of cirrhotic disease resulting from diseases such as alcoholism, nonalcoholic steatohepatitis, and hepatitis C.
Hou
Guoqing
G
Department of Human Genetics, University of Michigan Medical School, G061X MBNI, Ann Arbor, MI 48109, USA.
Dick
Robert
R
Brewer
George J
GJ
D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002252:Carbon Tetrachloride Poisoning / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003300:Copper / Q000378:metabolism*; D005260:Female; D006527:Hepatolenticular Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008982:Molybdenum / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors
D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; D002251:Carbon Tetrachloride