Effect of repeated exposure to aniline, nitrobenzene, and benzene on liver microsomal metabolism in the rat.

Exposure of rats to aniline at daily doses of 50 mg/kg of body weight over a month stimulated the microsomal metabolism as manifested by (1) acceleration of p-hydroxylation of anilin and N-demethylation of aminopyrine in 9-000 times g postmitochondrial supernatant of the liver, (2) shortening the sleeping time after hexobarbital, and (3) reduction of the antipyretic effect of phenacetin. In the rats exposed to nitrobenzene in a similar manner to aniline, nitroreduction of nitrobenzene and p-hydroxylation of aniline remained unaffected; the antipyretic effect of phenacetin was decreased, whereas hexobarbital sleeping time remained unchanged. Exposure of rats to benzene (50 mg/kg of body weight daily for a month) had no effect on the rate of hydroxylation of benzene and N-demethylation of aminopyrine. In benzene-exposed rats hexobarbital sleeping time was prolonged whereas the antipyretic effect of phenacetin was unaffected. Microsomal metabolism of aniline, nitrobenzene, and benzene was stimulated and inhibited when the rats were pretreated with phenobarbital and SKF 525-A, respectively.     

Vitamin A levels in regenerating rat liver. Effects on microsomal drug metabolism

After being maintained on a vitamin A-deficient or complete diet for a period of five weeks, male Sprague-Dawley rats were subjected to a two-thirds partial hepatectomy (PH) or sham operation. The vitamin A content of the liver of vitamin A-deficient, PH rats was below the limit of detection (less than 1 microgram/g liver). Rats fed the control diet and subjected to PH had hepatic levels of vitamin A that were 37% and 49% lower 48 and 72 hours after surgery, respectively, when compared with sham-operated controls. Hepatic microsomal cytochrome P-450 levels were significantly reduced in PH rats fed the complete diet 48 hours after PH and in PH rats fed either the deficient or complete diet 72 hours after. Vitamin A deficiency alone significantly reduced cytochrome P-450 levels. A combination of vitamin A deficiency and PH had the most dramatic effect on cytochrome P-450 and aminopyrine N-demethylase, which reduced the activity to approximately 50% of the activities found in the sham-operated control group. PH resulted in the greatest reduction in the rate of disappearance of benzo[a]pyrene in the presence of liver microsomes prepared from vitamin A-deficient rats.     

Vitamin A levels in regenerating rat liver. Effects on microsomal drug metabolism

After being maintained on a vitamin A‐deficient or complete diet for a period of five weeks, male Sprague‐Dawley rats were subjected to a two‐thirds partial hepatectomy (PH) or sham operation. The vitamin A content of the liver of vitamin A‐deficient, PH rats was below the limit of detection (< 1 μg/g liver). Rats fed the control diet and subjected to PH had hepatic levels of vitamin A that were 37% and 49% lower 48 and 72 hours after surgery, respectively, when compared with sham‐operated controls. Hepatic microsomal cytochrome P‐450 levels were significantly reduced in PH rats fed the complete diet 48 hours after PH and in PH rats fed either the deficient or complete diet 72 hours after. Vitamin A deficiency alone significantly reduced cytochrome P‐450 levels. A combination of vitamin A deficiency and PH had the most dramatic effect on cytochrome P‐450 and aminopyrine N‐demethylase, which reduced the activity to approximately 50% of the activities found in the sham‐operated control group. PH resulted in the greatest reduction in the rate of disappearance of benzo[a]pyrene in the presence of liver microsomes prepared from vitamin A‐deficient rats.     

Induction of microsomal enzymes in the rat liver by inhalation of hydrocarbon solvents

Summary The possibility of increase of microsomal enzyme activities in the liver by inhaled hydrocarbon solvents has been tested in preliminary investigations with male Wistar rats. The animals were exposed 5 hrs per day to an atmosphere containing various solvents, in a test period of 10 or 28 days. Dichloromethane, carbon tetrachloride, trichloroethylene, and benzene in a concentration of 450–500 ppm caused slight increases of cytochrome P₄₅₀ and/or of aminopyrine demethylase activity after 10 days (P>0.02). At a test period of 28 days already 50 ppm of carbon tetrachloride led to an increase of cytochrome P ₄₅₀ in the liver cell (P>0.02). It is reasonable to assume that with prolonged exposure even small solvent concentrations in the respiratory air may lead to undesirable alterations in biotransformation of foreign substances and endogenous compounds in the liver.     

Alterations in rat liver microsomal enzymes following exposure to carbaryl and malathion in combination

Pesticides are a part of man's and animal's diet. The air we breathe and the water we drink also provide us with added measurable doses. Pesticides produce changes in -glucuronidase (-glu) content, which is highly concentrated in the liver. A study was conducted to examine the effect of carbaryl and malathion in combination on liver microsomal enzymes. In vitro studies which incubated rat serum, rat liver homogenate or purified -glu enzyme with 2 or 4 mM carbaryl and/or malathion had no effect on the -glu activity.Treatment with 50 mg/kg carbaryl daily for one week produced a significant 40% decrease in whole liver homogenate -glu activity. A single administration showed only a slight decrease through the 24-hr period examined. Rat liver subcellular fractionation studies revealed a significant decrease of 50% in microsomal -glu content one hr after a single administration of 50 mg/kg carbaryl. This decrease was correlated with a subsequent decrease in the microsomal -glu levels and was noted after daily treatment for one week with 50 mg/kg carbaryl.Incubation of 4 mM carbaryl with microsomal suspensions revealed a release of the microsomal -glu enzyme, whereas 4 mM malathion exerted an inhibition on the release of this enzyme. The combination of carbaryl and malathion (4/4 mM) produced an effect between that caused by either pesticide alone. This effect was not significantly different from the vehicle control until 30 min after the addition of the pesticide combination. To further exemplify an effect on the endoplasmic reticulum, it was observed that 25 mg/kg carbaryl, as well as 25/ 25 mg/kg carbaryl/malathion induced the UDP-glucuronyl transferase activity following daily treatment for seven days. These results revealed a decrease in microsomal -glu activity and calcium was correlated with their respective increases observed in the serum.     

Induction of aortic plaques in guinea pigs by exposure to kerosene

Guinea pigs were exposed to kerosene aerosols or to smoke produced from kerosene under conditions approximating those in a kitchen. They were compared to controls exposed to saline aerosols or to atmospheric air. Both types of kerosene exposure engendered aortic plaques with fibrous tissue, collagen, and elastic fibers embedded in abundant glycosaminoglycans-rich ground substance, interspersed in which are smooth muscle cells resembling those seen in atherosclerosis, and changes in levels of blood lipids. The results suggest that chronic exposure to kerosene, a domestic fuel very widely used in many countries, may have important toxic effects in addition to the pulmonary effects that have been reported by others.     

Lymphohaematopoietic malignancies and quantitative estimates of exposure to benzene in Canadian petroleum distribution workers.

OBJECTIVE: To evaluate the relation between mortality from lymphohaematopoietic cancer and long term, low level exposures to benzene among male petroleum distribution workers. METHODS: This nested case control study identified all fatal cases of lymphohaematopoietic cancer among a previously studied cohort. Of the 29 cases, 14 had leukaemia, seven multiple myeloma, and eight non-Hodgkin's lymphoma. A four to one matching ratio was used to select a stratified sample of controls from the same cohort, controlling for year of birth and time at risk. Industrial hygienists estimated workplace exposures for benzene and total hydrocarbons, without knowledge of case or control status, for combinations of job, location, and era represented in all work histories. Average daily benzene concentrations ranged from 0.01 to 6.2 parts per million (ppm) for all jobs. Company medical records were used to abstract information on other potential confounders such as cigarette smoking, although the data were incomplete. Odds ratios (ORs) were calculated with conditional logistic regression techniques for several exposure variables. RESULTS: Risks of leukaemia, non-Hodgkin's lymphoma, and multiple myeloma were not associated with increasing cumulative exposure to benzene or total hydrocarbons. For leukaemia, the logistic regression model predicted an OR of 1.002 (P < 0.77) for each ppm-y of exposure to benzene. Duration of exposure to benzene was more closely associated with risk of leukaemia than other exposure variables. It was not possible to completely control for other risk factors, although there was suggestive evidence that smoking and a family history of cancer may have played a part in the risk of leukaemia. CONCLUSION: This study did not show a relation between lymphohaematopoietic cancer and long term, low level exposures to benzene. The power of the study to detect low-such as twofold-risks was limited. Thus, further study on exposures to benzene in this concentration range are warranted.     

Effect of folate deficiency on microsomal drug metabolism and heme content in the intestinal mucosa of guinea pigs

The relationship between folate deficiency, heme content, and microsomal drug metabolism in the intestinal mucosa of the guinea pig was examined. Weanling male guinea pigs were pair‐fed a folate‐deficient diet, and intestinal mucosal folate levels were measured. A significant decrease (75%) in these levels was observed at 3 weeks after diet initiation. A significant decrease (78%) in intestinal mucosal drug metabolism (7‐ethoxycoumarin O‐deethylase activity) and a significant decrease (46%) in intestinal mucosal heme content were also observed at this time. These findings indicate that folic acid deficiency in the guinea pig results in a marked reduction in heme content and microsomal drug metabolism of the intestinal mucosa.     

Interactions of m-xylene and aspirin metabolism in man.

In a series of experiments to investigate interactions between industrial solvents and common medications the interaction between m-xylene and aspirin was studied. As both these substances are metabolised and excreted as glycine conjugates there would possibly be competition for this conjugation pathway. Five male volunteers were exposed on separate occasions to m-xylene by inhalation (100 ppm), aspirin (1500 mg) by mouth, and m-xylene and aspirin together under controlled conditions in an exposure chamber. Urine and blood samples were collected and analysed for m-xylene, aspirin, and their metabolites. The amounts of the major glycine conjugates produced from m-xylene (m-methylhippuric acid) and aspirin (salicyluric acid) were significantly reduced by about 50% when m-xylene and aspirin were coadministered. There appears to be a mutual inhibition on the formation of the respective glycine conjugates. It is suggested that the inhibition is due to competition for either the enzymes, acyl-CoA synthetase, or glycine N-acylase. These findings have implications in the biological monitoring of workers exposed to m-xylene.     

Metabolic enzyme activities in fish gills as biomarkers of exposure to petroleum hydrocarbons.

Metabolic effects of low-level exposure of Atlantic salmon (Salmo salar) to the water accommodated fraction (WAF) of crude oil and to dispersed crude oil were studied. Aerobic enzymes citrate synthase and cytochrome C oxidase, and anaerobic enzyme lactate dehydrogenase were measured in gills during a 4-day exposure to low concentrations of dispersed Bass Strait crude oil and WAF, and during the following 8 days of depuration in clean seawater. Relative to pre-exposure levels, citrate synthase and lactate dehydrogenase exhibited a significant inhibition of activity during exposure to the WAF of crude oil, and to dispersed crude oil, while activity of cytochrome C oxidase remained unchanged. Citrate synthase activities returned to preexposure levels after 4 days following termination of exposure for the WAF-exposed fish, and after 2 days for the dispersed-oil-exposed fish. After the termination of exposure to both treatments, lactate dehydrogenase activity remained low relative to levels measured prior to exposure, which indicated that the activity of this enzyme may be a sensitive medium to long-term biomarker of exposure to petroleum-contaminated water bodies.     

Experimental study on the metabolism of triethylamine in man.

Five healthy volunteers were exposed by inhalation to triethylamine (TEA; four or eight hours at about 10, 20, 35, and 50 mg/m3), a compound widely used as a curing agent in polyurethane systems. Analysis of plasma and urine showed that an average of 24% of the TEA was biotransformed into triethylamine-N-oxide (TEAO) but with a wide interindividual variation (15-36%). The TEA and TEAO were quantitatively eliminated in the urine. The plasma and urinary concentrations of TEA and TEAO decreased rapidly after the end of exposure (average half time of TEA was 3.2 h). There was an excellent association between air levels of TEA and the urinary concentrations in samples obtained within two hours of the end of exposure. Thus the urinary level of TEA taken in this period is useful as a biological monitoring of exposure. An air concentration of 10 mg/m3 corresponds to an average urinary concentration of about 40 mmol/mol creatinine (at sedentary work).