Activity of delta8- and delta9-tetrahydrocannabinol and related compounds in the mouse.

The 11-hydroxy metabolites of Delta(8).- and Delta(9)-tetrahydrocannabinol are more active than the parent compounds when administered to mice by either the intravenous or intracerebral route. Both Delta(8)- and Delta(9)-tetrahydrocannabinol are rapidly and extensively metabolized by the liver and not by the brain. The hypothesis that the 11-hydroxy metabolites may be the active form of tetrahydrocannabinol is discussed

High-pressure liquid chromatography analysis of benzo(a)pyrene metabolism by microsomal enzymes from rhesus liver and lung.

The metabolism of benzo(a)pyrene was determined, using rhesus monkey hepatic and pulmonary microsomal enzymes. Metabolites were separated by high-pressure liquid chromatography and identified using known reference standards. Metabolites were quantitated by scintillation spectrometry. Both liver and lung microsomes metabolized benzo(a)pyrene to the following metabolites: 9,10-, 7,8-, and 4,5-dihydrodihydroxybenzo(a)pyrene; benzo(a)pyrene-1,6-dione, -3,6-dione, and -6,12-dione; and 9- and 3-hydroxybenzo(a)pyrene. Two unidentified metabolites and one metabolite region which chromatographed prior to 9,10-dihydrodihydroxybenzo(a)pyrene were produced by both liver and lung microsomes. The two unknown peaks were located between, 9,10- and 4,5-dihydrohidroxybenzo(a)pyrene. Two additional unknown metabolites were produced only in the liver and had retention times slightly greater than the 4,5- and 7,8-dihydrodihydroxybenzo(a)pyrene metabolites, respectively. Quantitative determination of benzo(a)pyrene metabolism revealed large differences for the three monkeys and the respective tissue activities. Liver activity for each animal was substantially higher than lung activity for all benzo(a)pyrene metabolites. The ratio of the metabolites also differed between the liver and lung. 3-Hdyroxybenzo(a) pyrene represented over 60% of the total liver metabolite fraction and 30% of the total lung metabolite fraction. The total quinone fraction represented between 7 and 13% of the total metabolites in the liver and comprised over 40% of the total lung metabolites. The metabolite ratios for the dihydrodiols were very similar for both tissues.

Distribution of delta 9-tetrahydrocannabinol in the mouse.

1. The distribution of Delta(9)-tetrahydrocannabinol-(14)C in the pregnant and nonpregnant mouse is very similar. High concentrations of radiolabel can be seen in the maternal liver, spleen, lungs, brown fat, adrenal glands, mammary glands, yolk sac placenta and corpora lutea. In the pregnant mouse Delta(9)-THC crosses the placenta and enters the foetuses in very low concentrations, with no apparent selective intrafoetal radiolabel accumulation sites. Autoradiograms showing the distribution of (14)C-cannabinoid 2 h after dosing are presented.2. A small amount of maternal liver and foetal tissue was removed from the mice, used for autoradiography and extracted with ethyl acetate. Most of the radiolabel in these tissues was solvent extractable and was separated by thin layer chromatography into two fractions, THC and metabolites.3. It appears that most of the cannabinoid is present in a free rather than conjugated form.

The use of high pressure liquid chromatography to study chemically induced alterations in the pattern of benzo[a]pyrene metabolism.

The metabolism of radiolabeled benzo[a]pyrene (BP) by control, 3-methyl-cholanthrene (3-MC) induced, and 1,1,1-trichloropropene-2,3-oxide (TCPO)-inhibited rat liver microsomes was measured using fluorescence, radiometric, and high-pressure liquid chromatographic (HPLC) assays. Significant differences in the total measurable metabolism of BP by the three microsomal enzyme incubations resulted from the use of the three assay procedures. Appreciable differences in the concentration of the metabolite fractions after 3-MC induction and TCPO inhibition are clearly demonstrated. NMR analysis revealed that while the 3-hydroxy-BP fraction is greater than 90% pure, the 9-hydroxy fraction contains a number of metabolites having essentially identical retention times.

A 6-month dietary toxicity study of acidic sodium aluminium phosphate in beagle dogs.

Sodium aluminium phosphate [NaAl3H14(PO4)8. 4H2O], a leavening acid, was administered to groups of six male and six female beagle dogs at dietary concentrations of 0, 0.3, 1.0 or 3.0% for 6 months. No adverse treatment-related clinical signs were observed. There were no statistically significant differences in mean body weights between test and control groups at any of the weekly determinations. Weekly mean food consumption values of all male treated groups did not differ significantly from those of the control group at any stage of the study. Statistically significant reductions in food consumption occurred sporadically in all treated groups of female dogs. No significant absolute or relative organ-weight differences were found between any of the treated groups and their respective controls. Haematological, blood chemistry and urinalysis data showed no toxicologically significant trends. Histopathological examination revealed no changes considered to be related to treatment. Thus dietary administration of sodium aluminum phosphate for 6 months at concentrations of 3% or lower caused no significant toxicological effects in beagle dogs.

Correlation of brain levels of barbiturate enantiomers with reported differences in duration of sleep.

The concentrations of R(+)-and S(-)-pentobarbital and R(+)-and S(-)-secobarbital were determined in the brain stem, hypothalamus, cerebellum and cortex of mice after i.v. administration. No regional differences in enantiomer concentration or barbiturate/metabolite ratio were observed to account for the substantial potency differences reported for the enantiomeric forms of pentobarbital and secobarbital. Stereoselective differences in the rate of enantiomer metabolism and in stereochemical fit to the central nervous system receptor are discussed as possible reasons for the differences in duration of action.

The metabolism of ftorafur in the beagle dog and rhesus monkey.

1. Ftorafur, a fluorinated pyrimidine nucleoside antimetabolite, is metabolized by the beagle dog and rhesus monkey to 5-fluorouracil, which is subsequently biotransformed to the corresponding nucleosides, to alpha-fluoro-beta-ureidopropionic acid, to urea and to CO2. 2. In the dog, urea was the primary urinary metabolite while in the monkey, alpha-fluoro-beta-ureidopropionic acid predominated. 3. The dog and monkey excrete about 35 percent of the recovered dose as CO2. 4. The possibility that ftorafur is a relatively inactive transport form of 5-fluorouracil is discussed.

Partial characterization of hepatic micorsomes from tupaia glis.

The dithionite difference spectrum of Tupaia microsomal cytochrome P-450-CO complex has an absorbance maximum at 449 nm, rather than at 450 nm as found for rat, rabbit, mouse, guinea pig, and human microsomes. N-octylamine difference spectroscopy showed the ratio of high- and low-spin forms of cytochrome P-450 to be different from that of the rat, indicating that the 449 nm absorption maximum might be due to a high concentration of the high-spin form, cytochrome P-448. The Tupaia microsomes demonstrated greater aryl hydrocarbon activity than microsomes prepared from male rats. These preliminary results suggest that Tupaia microsomes contain a modified terminal oxygenase which is responsible for the observed rapid metabolism of benzo[alpha]pyrene.

A subchronic toxicity study of Phosflex 51B in Sprague-Dawley rats.

Phosflex 51B is a flame retardant plasticizer that is blended with polyvinyl chloride films to effectively control product flammability. Its composition places it in the butylated triphenyl phosphate category. Previous studies have shown Phosflex 51B to have low acute toxicity, to lack teratogenic and mutagenic activity, and to not induce delayed peripheral neuropathy. The present study was conducted to determine the toxicity of Phosflex 51B after repeated dietary exposure. Four groups, each consisting of 20 male and 20 female Sprague-Dawley rats, received rodent diet containing either 0, 100, 400, or 1600 ppm for 90 days. Parameters measured include body weight, food consumption, clinical observations, hematology, clinical chemistry, and cholinesterase activity. Tissues were examined at necropsy for gross changes and were processed for microscopic pathology. There were no significant treatment-related effects on body weights, food consumption, hematology and clinical chemistry, or cholinesterase values. A significant increase was observed in the absolute and relative mean weights of livers in high-dose male rats, the mean relative liver weights of the high-dose female animals, the mean relative kidney weights of the high-dose male rats, and the mean absolute weights of the adrenal glands from high-dose female rats. Neither gross nor microscopic pathology examinations revealed tissue changes in these organs or in any other organs. Although increases in liver, kidney, and adrenal weights were observed in certain animals in the 1600-ppm high-dose group, the administration of Phosflex 51B did not result in significant treatment-related adverse effects at dietary dose levels of 100 and 400 ppm. The no-observable-effect level (NOEL) in this study is 400 ppm.

Dietary subacute toxicity of ethylene thiourea in the laboratory rat.

Ethylene thiourea (ETU) was fed to groups of rats at 0, 1, 5, 125 or 625 ppm for up to 90 days. Other groups of rats received either propylthiouracil (PTU; 125 ppm) or amitrole (50 ppm) in their diets as positive controls. Only those rats which received ETU at 125 or 625 ppm and those ingesting PTU or amitrole demonstrated a measurable toxic response. This toxicity was reflected as an alteration in thyroid function and a significant change in thyroid morphology. Ingestion of 625 ppm ETU or 125 ppm PTU resulted in very substantial decrease in serum triiodothyronine (T-3) and thyroxine (T-4). Marked increases in serum thyroid stimulating hormone (TSH) levels were found in the 625 and 125 ppm ETU rats, the 125 PTU rats, and the rats receiving amitrole, each time this hormone was measured. Rats which ingested 625 ppm ETU also exhibited a decrease in iodide uptake by the thyroid. While a statistically significant increase in serum T-4 and degree of thyroid hyperplasia was observed for rats ingesting 25 ppm ETU for 60 days, normal thyroid hormone levels and thyroid morphology was found in rats on 25 ppm ETU for either 30 or 90 days. Based on diochemical and microscopic changes examined, the no-effect level for dietary ETU in this 90-day study is considered to be 25 ppm.

1-(8-Methoxy-4,8-dimethylnonyl)-4-(1-methyl-ethyl)benzene (MV-678): a reversible inducer of rat hepatic microsomal drug metabolism.

MV-678 [1-(8-methoxy-4,8-dimethynonyl)-4-(1-methylethyl)benzene], a recently developed insect growth regulator, increased the hepatic cytochrome P-450-dependent monooxygenase enzymes that metabolize endogenous and exogenous chemicals. In an initial set of experiments, male and female rats received 0, 50, or 800 mg/kg X d of MV-678 by gavage for 3 d, and in a second set of experiments, male rats received 0, 50, or 800 mg/kg X d of MV-678 by gavage for 30 d. A significant increase in both absolute and relative liver weight, microsomal protein content, cytochrome P-450 content, NADPH-cytochrome P-450 reductase activity, and ethylmorphine N-demethylase activity was observed in male and female rats at the high dose level at 3 d. Similar increases were observed in the 800-mg/kg X d males at 30 d. Hepatocellular hypertrophy and proliferation of endoplasmic reticulum observed at both 3 and 30 d correspond to and was consistent with microsomal enzyme induction. Reversibility of both induction and changes in morphology was determined by measuring the same parameters in animals treated for 30 d after a 15- or 30-d recovery period. At 15 d recovery, all biochemical parameters at the high dose level, except relative liver weight and microsomal ethylmorphine N-demethylase activity, had returned to control levels. No significant differences between the control and high dose group animals were noted at 30 d recovery. The hepatocellular changes observed in the high-dose group at 30 d were less apparent at 15 d recovery, and absent at 30 d recovery.

Characterization of the hepatic microsomal mixed-function oxidase enzyme system in miniature pigs.

Hepatic microsomal protein, cytochrome P-450, UDP-glucuronyltransferase, ethylmorphine demethylase, aniline hydroxylase, and aryl hydrocarbon hydroxylase levels were measured in the 2-, 4-, 5-, 6-, and 8-month-old Hanford miniature pig. The activities or concentrations of all of the liver parameters measured had apparently reached their adult plateau level by 2 months of age. The use of the miniature pig in toxicology research programs is discussed.