The Analgesic Acetaminophen and the Antipsychotic Clozapine Can Each Redox-Cycle with Melanin

Melanins are ubiquitous but their complexity and insoly. has hindered characterization of their structures and functions. We are developing electrochem. reverse engineering methodologies that focus on properties and esp. on redox properties. Previous studies have shown that melanins (i) are redox-​active and can rapidly and repeatedly exchange electrons with diffusible oxidants and reductants, and (ii) have redox potentials in midregion of the physiol. range. These properties suggest the functional activities of melanins will depend on their redox context. The brain has a complex redox context with steep local gradients in O2 that can promote redox-​cycling between melanin and diffusible redox-​active chem. species. Here, we performed in vitro reverse engineering studies and report that melanins can redox-​cycle with two common redox-​active drugs. Exptl., we used two melanin models: a convenient natural melanin derived from cuttlefish (Sepia melanin) and a synthetic cysteinyldopamine-​dopamine core-​shell model of neuromelanin. One drug, acetaminophen (APAP)​, has been used clin. for over a century, and recent studies suggest that low doses of APAP can protect the brain from oxidative-​stress-​induced toxicity and neurodegeneration, while higher doses can have toxic effects in the brain. The second drug, clozapine (CLZ)​, is a second generation antipsychotic with polypharmacol. activities that remain incompletely understood. These in vitro observations suggest that the redox activities of drugs may be relevant to their modes-​of-​action, and that melanins may interact with drugs in ways that affect their activities, metab., and toxicities.