Effect of ascorbic acid esters on hepatic glutathione levels in mice treated with a hepatotoxic dose of acetaminophen.

Acetaminophen (APAP) with or without ascorbyl stearate (AS) or ascorbyl palmitate (AP) was administered by gavage to male Swiss-Webster mice at a dose of 600 mg/kg for each chemical. The biochemical markers of hepatotoxicity, serum transaminases (serum glutamate pyruvate transaminase [SGPT], serum glutamate oxaloacetic transaminase [SGOT]) and serum isocitrate dehydrogenase (SICD) activities were monitored after APAP and APAP + AP or AS dosing. There were significant reductions in serum transaminase and SICD activities in the APAP- + ascorbate ester-treated animals as compared to APAP-positive controls. Oral coadministration of APAP with AP or AS did not prevent the initial hepatic GSH depletion (15 min-4 hr postdosing). However, hepatic GSH content began to rise in the APAP + AS or AP-treated animals at 4 hr and reached control values within 12 hr postdosing. Urinary mercapturate conjugates were also significantly higher in the APAP + AP or AS-treated animals as compared to APAP alone when measured over a 60-min postdosing period. Plasma sulfobromophthalein (BSP) retention was approximately eight times higher in APAP-treated animals as compared to the APAP + ascorbate ester treatments indicating maintenance of hepatic excretory functions in presence of AP or AS. Prior depletion of hepatic GSH by diethyl maleate (DEM) did not alter hepatoprotective effects of AP or AS in the presence of APAP. Hepatic ascorbate levels also peaked at 4 hours after APAP + AP or AS treatments. The possible role of L-ascorbic acid esters in GSH regeneration following co-administration of a hepatotoxic dose and APAP is discussed.

The pattern of cadmium in the environment of five Minnesota cities.

This paper reports on the cadmium results of a soil survey conducted by the State of Minnesota during the summer of 1986. The survey collected soil-dust trom the oldest census tracts of Minneapolis, St. Paul, Duluth, St. Cloud and Rochester. The results reveal fundamental differences in soil cadmium among cities. Soil cadmium exceeds 2 µg g(-1) in 8.4% of the samples in Minneapolis, and 7.0, 4.0, 3.3 and 1.5% respectively of the samples collected in St. Paul, Duluth, St. Cloud and Rochester. Minneapolis and St. Paul residential houseside soil samples had cadmium levels that exceeded 2 µg g(-1) in 24.5 and 21.2% respectively of the samples collected. By comparison, the Minneapolis and St. Paul residential streetside soil samples had cadmium levels that exceeded 2 µg g(-1) in 1.2 and 0.6%, respectively, of the samples collected. Also the Minneapolis and St. Paul residential midyard soil samples had cadmium levels that exceeded 2 µg g(-1) in 1.9 and 5.5%, respectively, of the samples collected. Cadmium levels for the combined data for all cities and communities in Minneapolis appears to be directly related to traffic flow. However, cadmium levels around housesides and in midyards do not follow patterns of traffic flow in the same manner as cadmium content of soils along streetsides. St. Paul has an anomalously high cadmium content toward the east of the city compared with the west side of the city. The Pigs Eye sewage sludge incinerator located east of the city is the most likely source of cadmium to cause this pattern. This study provides essential urban background information about both the fundamental environmental patterns of cadmium as well as processes which appear to operate to cause those patterns.

Influence of ascorbic acid esters on acetaminophen-induced hepatotoxicity in mice.

Groups of male Swiss-Webster mice were gavaged with acetaminophen (APAP), APAP + ascorbyl stearate (AS), or APAP + ascorbyl palmitate (AP) at a dose of 600 mg/kg for each chemical. APAP alone caused a significant increase in liver weight/body weight ratio and hepatic glutathione (GSH) depletion. Co-administration of the ascorbate esters AP or AS with APAP prevented an increase in liver weight/body weight ratios and hepatic glutathione depletion. APAP + AS treatments caused significantly greater reductions in rectal temperature at 15-30 min post-dosing periods when compared to APAP + AP or AS treatments. Blood levels of APAP had the same relationship. The study indicates a correlation between APAP blood levels and antipyretic effect of APAP + AS and APAP + AP coadministrations. While both ascorbate esters probably afford protection against APAP-induced hepatotoxicity in mice by reducing the reactive intermediate back to the parent compound, the APAP + AS combination provides better therapeutic efficacy as an antipyretic at the 15-30 min post-dosing periods.

Potential neuromuscular toxicity of N'-(2,4-xylyl)-N-methyl formamidine HCl in rodents.

The mammalian neuromuscular toxicity of N'-(2,4-xylyl)-N-methyl formamidine hydrochloride (U-40481A) was evaluated by programmed screening. The LD50 for mice, determined 48 h after single, subcutaneous (s.c.) injections, was 107 mg/kg body wt. Acute toxicity signs included abnormal gait, hindlimb hyperextension, transient hyperactivity followed by a protracted phase of hypoactivity, ataxia, progressive respiratory difficulty, cyanosis, loss of righting reflex, and death. Relatively low doses of U-40481A (1, 5, 10, and 20 mg/kg, s.c.) markedly impaired the ability of trained mice to ride a rotating rod (rotarod). U-40481 (the base, 1-8 X 10(-4) M) reduced isometric contractions of the isolated rat hemidiaphragm obtained by supramaximal electrical stimulation of either the phrenic nerve or the diaphragm itself in a dose-dependent manner. The neurological deficit and motor incoordination signs observed during acute toxicity testing and in the rotarod study are, at least partly, due to the ability of U-40481A to (i) interfere with neuromuscular transmission, and (ii) decrease skeletal muscle contractility by a direct action on the muscle itself. These 2 effects may also be involved in U-40481A-induced mortality in mice.