naphthoquinones and naphthalene-1-2-oxide

Naphthalene is an important industrial chemical, which has recently been shown to cause tumors of the respiratory tract in rodents. It is thought that one or more reactive metabolites of naphthalene, namely, naphthalene-1,2-oxide (NPO), 1,2-naphthoquinone (1,2-NPQ), and 1,4-naphthoquinone (1,4-NPQ) contribute to the tumorigenicity of this chemical. These electrophiles are all capable of covalent binding to macromolecules including DNA and proteins. The stability of cysteinyl adducts of NPO, 1,2-NPQ, and 1,4-NPQ were investigated in both hemoglobin (Hb) and albumin (Alb) of male F344 rats following a single administration of 2 different doses (400 or 800 mg naphthalene per kg body weight). To assess the stability of Alb adducts, we compared the rates of NPO-Alb turnover (half-life of approximately 2 days) and 1,2-NPQ-Alb (half-life of approximately 1 day) to the normal turnover rate of Alb in the rat (half-life = 2.5-3 days). Based on the rapid turnover of these adducts relative to Alb itself, we concluded that they were unstable. However, the stability of Alb adducts was not affected by the dose of naphthalene administered (400 or 800 mg/kg). In contrast, NPO-Hb adducts were relatively stable (rate constant of adduct instability

Topics: Albumins; Animals; Biotransformation; Cysteine; Dose-Response Relationship, Drug; Half-Life; Hemoglobins; Male; Models, Biological; Naphthalenes; Naphthoquinones; Protein Binding; Rats; Rats, Inbred F344; Time Factors

Naphthalene-1,2-oxide (NPO), 1,2-naphthoquinone (1,2-NPQ) and 1,4-naphthoquinone (1,4-NPQ) are the major metabolites of naphthalene that are thought to be responsible for the cytotoxicity and genotoxicity of this chemical. We measured cysteinyl adducts of these metabolites in hemoglobin (Hb) and albumin (Alb) from F344 rats dosed with 100-800 mg naphthalene per kg body weight. The method employs cleavage and derivatization of these adducts by trifluoroacetic anhydride and methanesulfonic acid followed by gas chromatography-mass spectrometry in negative ion chemical ionization mode. Cysteinyl adducts of both proteins with NPO, and 1,2- and 1,4-NPQ (designated NPO-Hb and -Alb, 1,2-NPQ-Hb and -Alb, and 1,4-NPQ-Hb and -Alb, respectively) were produced in a dose-dependent manner. Of the two structural isomers resulting from NPO, levels of NPO1 adducts were greater than those of NPO2 adducts in both Hb and Alb, indicating that aromatic substitution is favored in vivo at positions 1 over 2. Of the quinone adducts, 1,2-NPQ-Hb and -Alb were produced in greater quantities than 1,4-NPQ-Hb and -Alb, indicating either that the formation of 1,2-NPQ from NPO is favored or that more than one pathway leads to the formation of 1,2-NPQ. The shapes of the dose-response curves were generally nonlinear at doses above 200 mg naphthalene per kg body weight. However, the nature of nonlinearity differed, showing evidence of supralinearity for NPO-Hb, NPQ-Hb and NPQ-Alb and of sublinearity for NPO-Alb. Low background levels of 1,2-NPQ-Hb and -Alb and 1,4-NPQ-Hb and -Alb were detected in control animals without known exposure to naphthalene. However, the corresponding NPO-Hb and -Alb adducts were not detected in control animals.

Topics: Acetylcysteine; Animals; Gas Chromatography-Mass Spectrometry; Hemoglobins; Humans; Male; Mesylates; Molecular Structure; Naphthalenes; Naphthoquinones; Protein Binding; Rats; Rats, Inbred F344; Sensitivity and Specificity; Serum Albumin

Naphthalene (NA) is metabolically activated to the reactive intermediates, naphthalene oxide (NO) and naphthoquinones. To investigate the role of circulating reactive metabolites in NA toxicity, the half-life of NO was examined. The in vitro half-life of NO in both whole blood and plasma was 10 min. Detectable levels of NO were seen in perfusate leaving the isolated perfused liver of B6C3F1 mice infused with 10 mumol/h NA. Identification of protein sulfhydryl adducts in NA-exposed mice (50 and 100 mg/kg, IP, 24 h) revealed a predominance of quinone adducts in liver, lung, kidney, red blood cells and brain. The epoxide adduct predominated in plasma protein. Administration of the sulfate conjugate of 1,4-dihydroxynaphthalene (NHQS) (100 mg/kg) resulted in formation of naphthoquinone protein sulfhydryl adducts in lung, liver and kidney. Administration of 1,4-naphthoquinone (NQ) (5 mg/kg) produced NQ adducts in liver, lung, kidney, plasma and brain.

Topics: Animals; Binding Sites; Brain; Half-Life; Hydroquinones; Kidney; Liver; Lung; Male; Mass Spectrometry; Mice; Naphthalenes; Naphthoquinones; Structure-Activity Relationship; Tissue Distribution