Administration of High Doses of Copper to Capuchin Monkeys Does Not Cause Liver Damage but Induces Transcriptional Activation of Hepatic Proliferative Responses

Abstract

Liver cells respond to copper loading upregulating protective mechanisms. However, to date, except for liver content, there are no good indicators that identify individuals with excess liver copper. We hypothesized that administering high doses of copper to young (5.5 mg Cu · kg⁻¹ . d⁻¹) and adult (7.5 mg Cu · kg⁻¹ . d⁻¹) capuchin monkeys would induce detectable liver damage. Study groups included adult monkeys (2 females, 2 males) 3-3.5 y old at enrollment treated with copper for 36 mo (ACu); age-matched controls (1 female, 3 males) that did not receive additional copper (AC); young monkeys (2 female, 2 males) treated from birth with copper for 36 mo (YCu); and young age-matched controls (2 female, 2 males) that did not receive additional copper (YC). We periodically assessed clinical, blood biochemical, and liver histological indicators and at 36 mo the hepatic mRNA abundance of MT2a, APP, DMT1, CTR1, HGF, TGFβ, and NFκΒ only in adult monkeys. After 36 mo, the liver copper concentration was 4-5 times greater in treated monkeys relative to controls. All monkeys remained healthy with normal routine serum biochemical indices and there was no evidence of liver tissue damage. Relative mRNA abundance of HGF, TGFβ and NFκB was significantly greater in ACu than in AC monkeys. In conclusion, capuchin monkeys exposed to copper at doses up to 50 times the current upper level enhanced expression of genes related to inflammation and injury without clinical, blood biochemical, or histological evidence of liver damage.

Interactive Effects of Copper and Functional Substances in Wine on Alcoholic Hepatic Injury in Mice

“…Thirdly, compared with WGs, there were no significant differences in T-AOC levels when the copper concentration was ≤0.99 mg/L ( p > 0.05). In the end, excessive copper concentrations (1.33 and 2.00 mg/L) significantly reduced T-AOC levels under all doses, which was consistent with the report by Araya et al (2012) that long-term high copper loading would lead to a reduction in relevant antioxidant capacity indicators [ 23 ].…”

Heavy Metals, Halogenated Hydrocarbons, Phthalates, Glyphosate, Cordycepin, Alcohol, Drugs, and Herbs, Assessed for Liver Injury and Mechanistic Steps

“…Analysis of hepatic content of copper provided very high values, suggesting copper as the causative agent in this patient. In animals, however, overdosed copper administration caused no liver injury as assessed by light microscopy [119][120][121] or only minimal, partially dose dependent changes such as small vacuoles of hepatocytes, hepatocyte swelling, inflammatory cells, or sinusoidal congestion [118]. Electron microscopy data on the liver of the patient exposed to high amounts of copper were not available [116,117] but have been reported in animal studies as irregularly shaped nuclei, abundant mitochondria, and displayed cristae, and hepatocytes with inclusion of secondary lysosomes [120].…”

“…Wilson disease is a genetic disorder of the liver leading to hepatic copper accumulation [3,4], and the earlier termed Indian childhood diseases were in fact cases of Wilson disease rather than caused by exposure to exogenous copper in drinking water or milk as previously assumed by error [114]. Experimental studies in animals showed mostly unchanged or in rare cases slightly increased serum ALT and AST activities after application of high copper amounts [118][119][120].…”

Regulation of Copper Transporters in Human Cells

“…High copper has an opposite effect on protein localization, but not under all circumstances. The decreased levels of mCTR1 at the PM were observed in the liver tissue with a prolonged (20 weeks) intracellular accumulation of copper (Ralle et al, 2010), whereas high dietary copper did not seem to have such an effect (Araya et al, 2012). Altogether, these observations raise an interesting possibility that under physiologically relevant conditions the distribution of CTR1 between the intracellular and PM pools is controlled by the metabolic demands of a cell (i.e.…”