Hepatorenal Disruption by Alkaloid Xenobiotics from Nauclea diderrichii: Biochemical, Histopathological, and In Silico ADMET Evidence.

Introduction: Despite its application in ethnomedicine and its considered safety, limited data exist on the toxicity of Nauclea diderrichii-enriched alkaloid fractions. This study evaluated the hepatorenal effects of an alkaloid-rich fraction from the plant's stem bark extract using in vivo and in silico approaches.

Methods: Alkaloids were extracted by an acid–base extraction procedure. The resulting fraction was analyzed by GC–MS, and the constituents were identified based on spectral matching as indole alkaloid–related compounds alongside pyridine-type alkaloids. Adult Wistar rats (n = 5 per group) were randomly divided into control and three treatment groups and orally administered the fraction at 100, 250, and 500 mg/kg body weight for 28 days. Dose levels were chosen on the basis of the reported LD₅₀. Biomarkers of hepatic and renal functions were measured, and the histopathological analysis of the tissues was carried out using the stain of hematoxylin-eosin. The identified alkaloids were subjected to in silico ADMET profiling.

Results: Treatment groups showed dose-related reductions in serum ALT, AST, urea, and creatinine levels (p < 0.05 at higher doses). However, histopathological examination revealed mild to moderate hepatocellular degeneration, inflammatory infiltration, and renal tubular alterations. This discrepancy suggests that reductions in biochemical markers may reflect enzyme modulation or adaptive responses rather than tissue protection, indicating that serum biomarkers alone may underestimate early or subclinical organ injury. GC–MS profiling supported the presence of indole and pyridine alkaloid–like constituents, and in silico ADMET predictions of these compounds indicated moderate oral bioavailability with a potential risk of hepatotoxicity.

Conclusion: Although reductions in biochemical indices were observed, histopathological lesions indicate that the alkaloid-rich fraction of Nauclea diderrichii may induce subclinical hepatorenal toxicity upon repeated exposure. The findings highlight a disconnect between serum biomarkers and tissue-level damage and underscore the importance of chemical characterization and safety evaluation of phytochemical fractions rather than crude extracts.