Horned Melon Extract Shows Liver Risk in Mice After Prolonged Use

The horned melon, a spiky orange fruit scientifically known as Cucumis metuliferus, has long been prized in parts of Africa for both its nutritional value and its traditional medicinal uses. Now a team of Nigerian researchers has put its safety credentials under the microscope, and the results paint a more complicated picture than many herbal enthusiasts might expect. In a study published in Discover Toxicology, scientists led by Joy Gararawa Usman of the University of Abuja and the National Veterinary Research Institute in Vom, Plateau State, found that while a single dose of the fruit’s aqueous extract appears remarkably safe in mice, weeks of repeated consumption can inflict measurable damage on the liver. The findings carry particular weight because, according to the World Health Organization, more than 80 percent of the world’s population, especially in low and middle income countries, relies on traditional medicine as its first point of care.

The fruit itself is something of a botanical curiosity. It comes in two distinct forms: a bitter wild type loaded with cucurbitacins, triterpenoid compounds that are highly toxic in large quantities, and a non bitter cultivated form that has gained international acceptance and is now grown commercially in countries such as New Zealand and Australia. The non bitter variety is rich in saponins, oily glycosides that foam when shaken with water and carry a mixture of medicinal properties and potential toxicity. Traditional practitioners have used decoctions of the root to relieve postpartum pain and to treat gonorrhea, while the fruit has been investigated for antimicrobial activity against Salmonella Gallinarum. Yet despite this long history of use, the authors noted a striking gap: almost no toxicological data existed for the fruit in mice, the workhorse animal of modern pharmacology.

To fill that gap, the team collected ripe fruits at the National Veterinary Research Institute, had them authenticated by a plant taxonomist at the University of Jos, and processed them into a powder that was extracted with distilled water using cold maceration over 72 hours. The resulting crude aqueous extract was then tested in Swiss albino mice of both sexes under protocols approved by the institute’s Animal Use and Care Committee. The researchers ran two complementary investigations: an acute toxicity test following Lorke’s method, in which mice received single oral doses ranging from 10 to 5000 milligrams per kilogram of body weight, and a 28 day sub acute study modeled on OECD guideline 407, in which one hundred mice were divided into a control group receiving distilled water and three treatment groups receiving daily doses of 200, 400, or 600 milligrams per kilogram.

The acute results were reassuring. Not a single mouse died or showed abnormal behavior at any dose, from the lowest to the highest, meaning the median lethal dose exceeds 5000 milligrams per kilogram. By the classification standards of Clarke and Clarke, natural substances with lethal doses in the range of 5000 to 15000 milligrams per kilogram are considered only slightly toxic, and OECD guidelines place compounds with values at or above 5000 milligrams per kilogram in class 5, the lowest toxicity category. The finding also aligns with earlier work in rats and cockerels, which similarly reported lethal doses above 5000 milligrams per kilogram for both aqueous and methanol extracts of the fruit. In other words, a one time dose of the ripe fruit extract is, by every measure applied here, remarkably benign.

The 28 day study told a subtler story. Body weights remained unchanged across all groups, suggesting the extract did not suppress appetite, an effect the authors attribute to phytochemicals such as alkaloids, flavonoids, and phenols that are known to regulate feeding. But the blood work revealed significant shifts. Red blood cell counts and packed cell volume rose markedly, with the highest dose group reaching a red cell count of 11.10 million cells per liter on day 21, up from 8.15 at baseline, and packed cell volume climbing from 48.54 percent to 65.11 percent. The researchers suggest these changes may reflect the fruit’s abundant iron, riboflavin, niacin, and amino acids, nutrients known to support red cell synthesis, and they speculate the fruit could hold promise as an anti anemia agent. Total white blood cells, by contrast, fell significantly at the highest dose, dropping from 8.84 to 2.66 billion cells per liter by day 21, alongside reduced lymphocyte counts, a pattern the authors interpret as a possible immunosuppressive effect.

The serum biochemistry raised the loudest alarm bells. Levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase, the classic trio of liver enzymes monitored in clinical practice, rose significantly across the treatment groups. Alanine aminotransferase is primarily liver specific and a reliable marker of liver disease, while aspartate aminotransferase, though found in many tissues, is sensitive to hepatic injury. Albumin and total protein declined, globulin climbed, and direct bilirubin fell at the highest dose. Taken together, these changes point toward liver damage or dysfunction, and the authors flag the presence of coumarins in the extract as a plausible culprit, since these compounds have been linked to hepatotoxicity despite their anticoagulant benefits.

Histopathology confirmed what the blood tests implied. Under the microscope, livers from treated mice showed congestion of hepatocytes at every dose tested, and at 400 milligrams per kilogram the tissue displayed slight necrosis, the death of liver cells. The kidneys and intestines, however, remained structurally normal at all doses. That renal resilience was echoed in the chemistry: urea and creatinine, the standard indicators of kidney function and protein metabolism, actually decreased significantly during treatment. The authors suggest that flavonoids and quinones in the fruit, which scavenge reactive oxygen species and promote diuresis, may exert a nephroprotective effect, consistent with earlier reports of kidney protection from methanol extracts of the fruit in cockerels.

The electrolyte data added one more layer of complexity. Serum sodium rose significantly at the highest dose, from 129.76 to 141.36 milliequivalents per liter by day 28, and chloride increased across all treatment groups. Elevated sodium and chloride can signal dehydration or kidney damage, but since the treated mice showed no dehydration and their kidney tissue appeared normal, the researchers point to another explanation: the fruit itself is rich in sodium, with previous analyses reporting roughly 8.9 to 16.7 milligrams of sodium per 100 grams of seed, so dietary intake from the extract may simply have raised circulating levels directly.

The overall verdict is a cautionary tale about the difference between a single dose and sustained use. The aqueous extract of Cucumis metuliferus appears safe within 24 hours, may support red blood cell production, and shows no signs of harming the kidneys, but prolonged administration risks liver injury, a conclusion consistent with earlier reports of hepatic and renal toxicity in cockerels and rats given extended courses of the extract. The authors emphasize that their findings apply to unrefined, crude extracts, whose chemical composition can vary widely, and they call for further research to identify the specific phytochemicals responsible for both the beneficial hematological effects and the hepatic damage. For the millions of people who turn to traditional plant remedies first, the spiky horned melon now comes with a clearer, and more nuanced, safety label: fine in a pinch, potentially harmful as a daily habit.

Subject of Research: Acute and sub-acute oral toxicity of the aqueous extract of ripe Cucumis metuliferus fruit in Swiss albino mice

Article Title: Toxicity assessment of the ripe fruit of Cucumis metuliferus in Swiss albino mice

Article References: Usman, J. G., Gadzama, U. N., Thliza, C. B., Elisha, I. L., Barde, I. J., Onakpa, M. M., Sanni, S., & Ajagbonna, O. P. (2025). Toxicity assessment of the ripe fruit of Cucumis metuliferus in Swiss albino mice. Discover Toxicology, 2(1), Article 5. https://doi.org/10.1007/s44339-025-00021-1

Image Credits: AI Generated

DOI: 10.1007/s44339-025-00021-1

Keywords: Cucumis metuliferus, horned melon, toxicity, hepatotoxicity, Swiss albino mice, acute toxicity, sub-acute toxicity, hematology, liver enzymes, nephroprotection, traditional medicine, aqueous extract