Ugandan Medicinal Plants Show Hidden Liver Risks in Rat Safety Tests

Across rural Uganda, three native plants have long been trusted allies against bacterial skin infections. Erlangea tomentosa, known locally as ekyoganyanja or kisula, Plectranthus caespitosus, and Psorospermum febrifugum, the so-called Christmas berry, are prepared as water decoctions or topical pastes and applied to everything from sores to allergic rashes. Their antibacterial credentials are real: earlier laboratory work by the same research team at Makerere University showed that extracts of all three plants inhibit Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Salmonella typhi, with minimum inhibitory concentrations between 3.12 and 12.5 milligrams per millilitre, alongside antioxidant activity and measurable sun protection factors. Yet a remedy that kills bacteria is only half the story. What the body pays for that benefit has, until now, been almost entirely unknown, and a new toxicology study published in Discover Toxicology suggests the answer is more complicated than traditional use implies.

The research team, led by Jane Namukobe and Moses Murungi of Makerere University’s Department of Chemistry, set out to fill that gap using Wistar albino rats, the standard mammalian workhorse of preclinical safety testing. Plant material was collected between April and June from Mpanga Central Forest Reserve and Mabira Forest, authenticated at the Makerere University herbarium, and processed into two very different preparations. Aqueous extracts, made by warm maceration in water at 40 degrees Celsius, were reserved for oral toxicity testing because that is how the plants are traditionally consumed. Organic extracts, prepared with a one-to-one mixture of dichloromethane and methanol, were used for dermal testing because topical remedies are typically blended with vehicles such as petroleum jelly. This design choice matters: what is safe to swallow and what is safe to smear are separate questions, and the study treated them as such.

The testing regime followed Organisation for Economic Co-operation and Development guidelines with slight modifications. For acute toxicity, rats received single oral doses of 2000 or 5000 milligrams per kilogram of body weight, or single dermal doses of 8000 or 10,000 milligrams per kilogram. For repeated-dose studies, animals were dosed daily with 200 or 400 milligrams per kilogram orally for 28 days, or 2000 and 5000 milligrams per kilogram dermally for 21 days. Throughout the studies, researchers recorded clinical observations, tracked body weights weekly, and then euthanised the animals for a full workup: blood chemistry covering liver and kidney markers, organ weights, and histopathological examination of the liver, kidneys, heart, stomach and small intestines. Skin irritation was scored with the Draize system, and sensitisation was probed with a modified mouse ear swelling test using tape stripping to heighten immune responses.

The headline finding is deceptively reassuring: no animal died, and no acute toxicity was observed for any extract by either route. Plectranthus caespitosus emerged as the standout performer. Its aqueous leaf extract produced no clinical signs, no changes in body or organ weights, no biochemical abnormalities and clean histopathology even after 28 days of repeated oral dosing. Dermal application caused neither irritation nor sensitisation. This is the first toxicity study ever conducted on this species, and the result aligns with related Plectranthus species such as P. neochilus and P. amboinicus, which have similarly shown wide safety margins in rodents. For a plant already used against skin allergies, the data make a strong case for pushing its active compounds toward antibacterial and skincare applications.

Erlangea tomentosa tells a more troubling story. A single oral dose of its leaf extract, even at the maximum 5000 milligrams per kilogram, caused only transient effects: elevated respiration, reduced mobility and increased urination that resolved within 24 hours. But repeated oral exposure at 400 milligrams per kilogram produced moderate to severe multifocal necrotizing hepatitis, literally patches of dying liver tissue, along with hyperplasia of goblet cells in the small intestine and sloughing of intestinal villi. Remarkably, the liver damage was invisible in the blood chemistry: bilirubin, creatinine and alkaline phosphatase levels remained statistically indistinguishable from controls, and the ALT-to-ALP ratio stayed below 10. The researchers attribute this mismatch to the liver’s known capacity for rapid biochemical recovery once a necrotizing agent is withdrawn, a phenomenon documented in drug-induced liver injury literature. Histopathology, in other words, caught what blood tests missed.

Repeated dermal exposure to E. tomentosa’s organic extract added another layer of concern. Although the extract was classified as a non-irritant with a primary irritation index below 1.5 and provoked no sensitisation in the ear swelling test, animals dosed repeatedly at 200 and 400 milligrams per kilogram developed necrotizing liver hepatitis. Blood chemistry showed significantly reduced ALT, ALP and urea alongside elevated bilirubin, a pattern the authors note can indicate cholestasis or impaired bile clearance, though reduced transaminases can also reflect hepatoprotective effects. The team points to historical reports of the plant’s toxicity to rabbits, in which fatal doses caused abdominal ascites and congestion of the liver, kidneys and lungs. Phytochemical screening offers a plausible mechanism: the extract contains tannins and anthraquinones, both of which have been shown to induce hepatic necrosis at sufficient concentrations, while its saponins may partially counteract that damage.

Psorospermum febrifugum, the stem bark remedy used across tropical Africa for skin diseases and wounds, occupied a middle ground. Acute oral exposure at 5000 milligrams per kilogram increased liver weight and temporarily raised respiration, urination and mobility, all resolving within a day. Repeated oral dosing at 400 milligrams per kilogram reduced both liver and kidney weights and produced a roughly three-fold increase in the AST-to-ALT ratio, a signature that typically signals hepatocellular injury or stress, together with elevated total and direct bilirubin. Yet histopathology of the liver showed no significant lesions, a discrepancy the researchers interpret as either adaptive organ remodelling, the liver’s regenerative capacity masking early damage, or the slow onset of chronic toxicity. The plant’s tannins and saponins, with their opposing effects on liver tissue, may explain why the tissue looked healthy even as enzyme levels flagged distress.

The dermal picture for P. febrifugum was arguably the most clinically significant. Topical application caused no skin irritation or sensitisation, but repeated exposure at 2000, 5000 and 8000 milligrams per kilogram significantly increased bilirubin, creatinine and AST while decreasing urea and ALP, a combination the authors link to drug-induced cholestasis and impaired kidney function. Acute exposure at 8000 milligrams per kilogram also disturbed sodium and potassium levels. The organic extract is rich in steroids, compounds known to induce or aggravate acute kidney injury, chronic kidney disease and glomerular toxicity, providing a chemical suspect for the renal findings. These results are notable because they emerged from skin application alone, demonstrating that a plant remedy can damage internal organs without ever touching the digestive tract, a fact with real implications for how topical herbal medicines are regulated.

The broader lesson of the study is that safety cannot be inferred from tradition, efficacy, or even a single toxicity endpoint. All three plants passed the most visible tests, no mortality, no acute toxicity, no skin irritation, yet repeated exposure revealed liver and kidney liabilities in two of them, and in E. tomentosa the worst damage appeared only under the microscope. The authors recommend that P. caespitosus advance toward development of antibacterial products and skincare formulations, while E. tomentosa and P. febrifugum require further work to isolate and characterise their toxic constituents, with tannins flagged as the most likely culprits. As antimicrobial resistance drives patients and researchers alike back toward plant-based remedies, this study stands as a cautionary benchmark: the dose, the route and the duration of exposure all matter, and a herbal medicine is only as safe as its most thorough toxicological evaluation.

Subject of Research: Oral and dermal toxicity assessment of three Ugandan ethno-medicinal plants used to treat bacterial skin infections, tested in Wistar albino rats

Article Title: Assessment of oral and dermal toxicity of selected ethno-medicinal plants used to treat bacterial skin infections in Uganda using Wistar albino rats

Article References: Assessment of oral and dermal toxicity of selected ethno-medicinal plants used to treat bacterial skin infections in Uganda using Wistar albino rats. (n.d.). https://doi.org/10.1007/s44339-024-00015-5

Image Credits: AI Generated

DOI: 10.1007/s44339-024-00015-5

Keywords: ethnomedicine, toxicology, Uganda, medicinal plants, hepatotoxicity, nephrotoxicity, Wistar rats, skin infections, phytochemistry, OECD guidelines, dermal toxicity, antimicrobial resistance