Kjell Aarstad

The clinical value of drug analyses in deliberate self-poisoning

1. In a prospective, unselective study of self-poisoned patients in 1978 and 1987 blood samples for drug analyses were drawn on admission in 265 and 400 cases, respectively. 2. The results from the drug analyses were compared with the clinical information obtained on admission. The main drug taken was identified on admission in 228 (86%) in 1978 and in 383 cases (96%) in 1987 (P < 0.001). 3. The clinical impression was completely in accordance with the results from the drug analyses in 192 cases (72%) in 1978 and 232 cases (58%) cases in 1987 (P < 0.001). The discrepancies mainly involved secondary drugs. 4. There was no significant difference in the clinical course of the poisonings in situations where the correct main drug was identified on admission and where the wrong main drug was suspected. 5. Knowledge of the correct drugs used when admitted would not have prevented complications or deaths. 6. We conclude that extensive pharmacological drug analyses play a limited role in the routine management of patients admitted for deliberate self-poisoning.

A comparison of the binding and distribution of benzo[a]pyrene in human and rat serum

Uptake and distribution of benzo[a]pyrene (B[a]P) in human and rat serum were studied by incubation, gel filtration and ultracentrifugation. A maximum uptake of 230 and 120 micrograms B[a]P/ml was found for human and rat serum, respectively. Of the B[a]P uptake about 1% was irreversibly bound to serum constituents from both species. The uptake of B[a]P by the lipoproteins was 90-95% and 80-85% for human and rat serum, respectively, the remainder being bound to albumin. In human serum B[a]P was mainly associated with low density lipoproteins (44-47%) while in rat serum with high density lipoproteins (40-54%). However, the distribution of B[a]P between the different lipoprotein fractions showed a high correlation with the concentration of cholesterol for both species. The present results demonstrate a serum uptake capacity of B[a]P for both species which exceeds any known occupational exposure. The extensive association between B[a]P and lipoproteins may have implications for the availability of B[a]P for metabolizing organs, an area which should be further investigated. As far as the total serum uptake and distribution of B[a]P are concerned, the rat seems to be an acceptable animal model for extrapolation of in vivo results to man.

Species differences in short term toxicity from inhalation exposure to bromobenzene

Lung, liver and kidney injury were studied in mice, rats and rabbits 48 h after termination of a 4 h inhalation exposure to bromobenzene vapour (250–3400 ppm). Light and electron microscopy of lung tissue revealed injury to Clara cells and adjacent epithelium in mouse bronchioli (bromobenzene concentration 250 ppm and 1000 ppm) and to Clara cells of rat bronchi and bronchioli (1000 ppm bromobenzene) and of rabbit bronchi (2500 ppm and 3400 ppm). Histological and clinicochemical indices of liver damage were found in the same animals, whereas kidney toxicity was observed in mice (two out of ten showed tubular necrosis and elevated concentration of plasma urea) and rats (all had elevated plasma concentrations of creatinine) exposed to 1000 ppm bromobenzene. Inhalation exposure thus produced less kidney injury than expected from previous studies with equimolar doses given intraperitoneally. The mouse was the most severely affected species, followed by the rat, and lastly the rabbit. The animal susceptibility could not be ranked according to the rate of14C-bromobenzene covalent binding in lung or liver, but it was inversely related to the rate of N-demethylation of benzphetamine (indicative of P450IIB activity) in both lung and liver microsomal preparations. Differences in a P450 mediated detoxification could therefore be of importance in species variability to bromobenzene injury.

Induction of Microsomal Enzymes after Inhalation of Methanol

Inhalation of 200, 2,000, and 10,000 ppm methanol increased several parameters in the microsomal cytochrome P-450 enzyme system in liver, lung, and kidney in a dose related manner. The most pronounced effect was observed in the kidney with an increase of 51% in the cytochrome P-450 concentration compared with the control. Cytochrome b5 and NADPH cytochrome c reductase showed the same pattern of induction. The microsomal metabolism of n-hexane was enhanced in liver and kidney with the highest increase in the formation of the neurotoxic and preneurotoxic metabolite 2-hexanol with an increase of 41 and 17%, respectively, after inhalation of 10,000 ppm. A decreased formation of all n-hexane metabolites was observed in the lung. These results indicate an inter-organ difference in the induction pattern of methanol exposure.

Inhalation of Butanols: Changes in the Cytochrome P-450 Enzyme System

After inhalation of different butanol isomers for 3 days (2000 ppm) and 5 days (500 ppm), liver and kidney parameters of the microsomal cytochrome P-450 enzyme system were increased. sec-Butanol caused the highest increase in cytochrome P-450 concentration with a 47% rise in the kidneys (500 ppm for 5 days) and 33% in the liver (2000 ppm for 3 days). A concomitant increase of the in vitro n-hexane metabolism in liver microsomes was observed with a 77% increased formation of the preneurotoxic metabolite 2-hexanol compared with control. iso-Butanol did not alter total cytochrome P-450 concentration but caused a significant 30% decrease in the formation of 2-hexanol. Inhalation of all butanols slightly decreased the enzyme levels in the lung. Changes in microsomal enzymes did not correlate with measured serum concentrations of the different butanols showing different inducing capacities among the butanol isomers themselves or the participation of metabolites in the inducing process. As a conclusion sec-butanol, probably through its metabolite methyl-ethyl-ketone, is the most potent inducer of microsomal cytochrome P-450 in liver and kidney while iso-butanol does not alter total cytochrome P-450.

Inhalation of isopropanol: Induction of activating and deactivating enzymes in rat kidney and liver. Increased microsomal metabolism of n-hexane

Rats were exposed to isopropanol by inhalation of 200,2000 and 8000 ppm for 2 weeks with a daily exposure of 6 h. A pilot group exposed to 8000 ppm was given a recovery period of 4 weeks. Kidney and liver microsomal metabolism of n-hexane was investigated in vitro concomitant with activities of cytochrome P-450 and GSH enzymes and blood concentration of isopropanol and its metabolite acetone. A dose dependent increase was observed in the formation of all metabolites of n-hexane in both organs. Of special interest was the 9%, 80% and 198% increase of the preneurotoxic metabolite 2-hexanol in kidney microsomes. Cytochrome P-450 was increased 14%, 40% and 43% in kidney after 200, 2000 and 8000 ppm, respectively, and 10% and 19% in liver at 2000 and 8000 ppm. The activity of glutathione S-transferase was unaffected in kidney but elevated in liver, while GSH levels were elevated in both organs. The elevated level of kidney cytochrome P-450 did not return to normal during the 4-week-recovery period in contrast to liver cytochrome P-450. It is thus indicated that cytochrome P-450 and associated microsomal enzymes are more easily inducible and the changes more persistent in kidney than in liver. Our observations suggest that cytochrome P-450-mediated metabolic activation of n-hexane in the kidneys may have toxicological relevance in addition to liver metabolism, and that coexposure to isopropanol and n-hexane may represent an enhancement of the health hazard from n-hexane, possibly due to the isopropanol metabolite acetone.

Increased Microsomal Metabolism of n-Hexane in Rat Kidney and Liver After Inhalation of Isopropanol

Inhalation of 200, 2,000, and 8,000 ppm isopropanol for 2 weeks enhanced the in vitro metabolism of n-hexane in microsomal preparations. The formation of the preneurotoxic metabolite 2-hexanol increased 9, 80, and 198%, respectively, in the kidney and 9, 22, and 132% in the liver. The concentration of cytochrome P-450 was also increased in a dose-dependent way with increases of 14, 40, and 43%, respectively, in the kidney and 6, 12, and 18% in the liver. The present investigation demonstrates similar effects of isopropanol after inhalation on kidney and liver microsomal enzymes. In both organs isopropanol was shown to potentiate the formation of neurotoxic metabolites from n-hexane. However, cytochrome P-450 appears to be more easily induced in kidney than in liver.

Lung and Liver Damage in Mice After Bromobenzene Inhalation: Effects of Enzyme Inducers

AbstractMice were pretreated With the enzyme inducers phenobarbital (PB), polychlorinated biphenyls (PCB) or β-naphthoflavone (BNF), and subsequently exposed to bromoben-zene (BrBz) at 250 and 7000 ppm in inhalation chambers for 4 h. In vivo lung and liver damage were evaluated and compared with results from in vitro covalent binding studies using lung and liver microsomes from mice given the same pretreatments. Reduced lung injury was observed in mice pretreated with PB and PCB compared to controls, whereas BNF pretreatment resulted in decreased liver injury. There were no correlation between the rates of in vitro covalent binding to pulmonary microsomes and the degree of lung injury. However, the slower rate of in vitro binding to liver microsomes compared to controls correlated with the decreased hepatic injury in BNF pretreated mice. An interesting relationship was found in PB- and PCB-pretreated mice between increased rates of covalent binding of bromobenzene to liver microsomes and a decrease in in ...