Calcium transport, thiol status, and hepatotoxicity followingN‐nitrosodimethylamine exposure in mice

Abstract

The hepatotoxicant N-nitrosodimethylamine (NDMA) is presumed to exert toxicity through reactive metabolites. NDMA is similar in this respect to numerous other hepatotoxicants, for which hepatotoxicity is also associated with a rapid depletion of soluble and/or protein thiols, and an inhibition of calcium transport systems. We examined the hypothesis that hepatotoxicity for NDMA is preceded by thiol depletion and/or inhibition of calcium transport in isolated liver subcellular fractions. Centrizonal liver necrosis in mice was evident at 24 but not at 12 h subsequent to intraperitoneal administration of 40 mg NDMA/kg. Hepatotoxicity was not preceded by depletion of liver protein-free sulfhydryls, nor by protein sulfhydryl depletion in liver whole homogenate, microsomal, or plasma membrane fractions. NDMA-mediated toxicity was also not preceded by inhibition of calcium uptake capability by microsomal, mitochondrial, or plasma membrane fractions. In contrast, carbon tetrachloride produced the expected rapid decrease in microsomal calcium uptake capability, followed by a centrizonal necrosis that was maximal at about 24 h. These studies suggest that the mechanism of NDMA hepatotoxicity may differ from that of a number of other hepatotoxicants (e.g., carbon tetrachloride, acetaminophen, bromobenzene) for which toxicity is also mediated through reactive metabolites.

N-Nitrosodimethylamine-Mediated Formation of Oxidized and Methylated DNA Bases in a Cytochrome P450 2E1 Expressing Cell Line

“…N -Nitrosodimethylamine (NDMA), the simplest and most widely occurring nitrosamine, has been shown to be an acute hepatotoxin and potent carcinogen in a variety of animal species and humans ( − ). It is generally believed that the metabolic activation of NDMA to reactive intermediates by cytochrome P450 2E1 is required for it to exert its carcinogenic and hepatotoxic effects ( , ).…”

CDP‐choline circumvents mercury‐induced mitochondrial damage and renal dysfunction

“…The role of membrane protein sulfhydryl groups on permeability is widely known. In fact, there is a large body of evidence in favor of thiol group participation in the control of mitochondrial Ca 2+ transport, for example, Chávez and Holguín (), Reitman et al (), and Moore et al (). In previous work, we demonstrated that the binding of Hg 2+ to proteins with molecular weights between the ranges of 20–30 kDa induces the opening of a non‐specific pore (Chávez and Holguín, ).…”

Evidence for the presence of active cytochrome P450 systems in Schistosoma mansoni and Schistosoma haematobium adult worms

“…NDMA has been shown to be an acute hepatotoxin and a potent carcinogen in many animal species and also potentially in humans [16,17]. In experiments with human liver microsomes, it has been demonstrated that cytochrome P450 2EI is the major enzyme responsible for the oxidative demethylation of NDMA at low substrate concentrations [18].…”