Extensive Alteration of Genomic DNA and Rise in Nuclear Ca²⁺ in Vivo Early after Hepatotoxic Acetaminophen Overdose in Mice

Abstract

Much attention has fallen upon Ca²⁺ and the critical role it appears to play in the process of lethal cell injury (Schanne et al., 1979; Moore, 1980; Jewell et al., 1982). Ca²⁺ appears to serve as the principal intracellular messenger that conveys initial damage arising from alkylation or peroxidation to discrete secondary sites that are essential to cell viability. Nonetheless, several aspects of the Ca²⁺ hypothesis of cell death remain elusive, including the location of initially damaged Ca²⁺ regulatory sites important to cell death, and the actual identity of the vital function or functions that deteriorate under excessive Ca²⁺ activity. Cell death is believed to occur via two distinct processes; apoptosis, or the programmed cell death seen during physiological events such as organ development and cell renewal, and necrosis, or the unprogrammed cell death that follows substantive pathologic insult (Wyllie, 1980; Duvall and Wyllie, 1986). A number of the steps leading to apoptosis in immature thymocytes are well defined. These include Ca²⁺ influx into the cell, endonuclease activation in the nucleus, and DNA degradation into periodic fragments not seen in necrosis (Cohen and Duke, 1984; McConkey et al., 1988a). The present study assesses whether acetaminophen-induced liver necrosis may share certain key steps in common with the process of apoptosis. Toxic doses of acetaminophen are known to cause Ca²⁺ to accumulate in liver and cytosolic Ca²⁺ activity to rise within 2 hr (Corcoran et al., 1987, 1988). We now examine the nucleus for lethal actions of unchecked Ca²⁺ activity in acetaminophen-induced necrosis, and we specifically monitor genomic DNA as a critical secondary target in this form of cell death.