Effects of Four Marine Toxins on Murine Hepatic Biotransformation Enzymes

This study assesses the impact of sublethal levels of four marine toxins ciguatoxin (CTX-1), maitotoxin-2 (MTX-2), saxitoxin (STX) and brevetoxin-2 (BTX-2) on murine hepatic detoxification enzymes expressed in mouse liver. CTX-1, BTX-2, and STX altered hepatic detoxification responses, but their effects were generally more limited or temporally variable than those observed with MTX-2. CTX-1 produced time-dependent changes in cytochromes P450 (CYPs)-associated activities, BTX-2 induced early CYP1A2 and CYP3A11 responses followed by later suppression, and STX reduced CYP1A2 and CYP3A11 while increasing microsomal reductase activities. Of these toxins, MTX-2 exhibited the highest toxicity, notably decreasing key proteins such as CYPs, including CYP1A2 and CYP3A11. CYP enzymes are vital for metabolizing important endogenous and various xenobiotic substances, including therapeutic drugs. After MTX-2 exposure, both CYP1A2 and CYP3A11 levels dropped significantly at 12 h (p < 0.0001 for CYP3A11, p < 0.0001 for CYP1A2). Histopathological analysis revealed liver damage; however, albumin mRNA levels remained stable post-MTX-2 treatment, indicating that hepatotoxicity was not the sole cause of CYP3A11 reduction. Immunohistochemical analysis displayed uniform CYP3A11 distribution across liver regions after MTX-2 treatment. This suggests that MTX-2 exposure could augment the toxicity of drugs like Aldactone, Erythromycin, and Cyclosporine that utilize this metabolic pathway in humans. This is the first type of research performed of this nature, which could add to our understanding of marine toxin metabolism. These findings provide additional toxicological insights into the effects of four marine toxins on detoxification enzymes, with particular interest in MTX-2 toxicity, and potential implications for the treatment of fish poisoning, including ciguatera fish poisoning.