Cardiotoxicity mechanisms from the point of view of preclinical or premarketing safety evaluation.

Abstract

The most commonly occurring cardiotoxic reactions in humans are due to over-exposure to chemicals that affect physiological function of the heart. These effects, which are usually receptor-mediated, are dose related and can generally be predicted from safety studies in animals. Direct chemical toxicity is initiated by an interaction of a reactive metabolite of the xenobiotic with cellular macromolecules. The incidence of such cardiotoxicity is low because few of these chemicals are metabolized in the heart. The concentration of cellular protective substances influences the development of such toxicity, and therefore species variation should be considered in safety studies. Chemically induced immune system-mediated reactions can develop in the heart, and may occur in anaphylaxis. Antibody mediated cytotoxic or immune complex reactions are rare events, and the predictability is poor. In some instances sensitivity is immunogenetically controlled. Cardiotoxic effects can also develop after prenatal exposure to chemicals, and thus consideration should be given to examining the offspring for those effects in teratology studies.