Increase In Relative Liver Weight Research Articles

The relationship of ornithine decarboxylase and thymidine kinase to mirex-induced liver growth.

To investigate the sequence of events that occur in the liver during mirex-induced adaptive liver growth, [3H]thymidine incorporation into DNA, thymidine kinase (TK), and ornithine decarboxylase (ODC) were studied in intact and adrenalectomized (ADX) mirex-dosed rats, and the responses were compared with experimental groups receiving corticosterone. In intact mirex-dosed rats (a response that is both hyperplastic and hypertrophic) there was a 36-h peak in ODC activity, and a 48-h peak in both [3H]thymidine incorporation into DNA and TK activity. This was accompanied by a 72% increase in relative liver weight (RLW). In contrast, in ADX mirex-dosed rats (a predominately hyperplastic response), there was a biphasic ODC response (18- and 36-h peaks), a 36-h TK peak, and a 48-h peak in [3H]thymidine incorporation into DNA. Both TK activity and [3H]thymidine incorporation into DNA were significantly elevated for the remainder of the 96-h study period. There was a 38% increase in RLW. Corticosterone supplements to mirex-dosed intact rats resulted in a biphasic peak of TK activity (30- and 48-h peaks), a reduced ODC peak at 36 h, and a 48-h peak in [3H]thymidine incorporation into DNA. RLW response was similar to the response in intact mirex-dosed rats. Corticosterone supplements to mirex-dosed ADX rats eliminated the 48-h peak of [3H]thymidine incorporation into DNA, reduced TK activity and shifted the peak to 30 h, and eliminated the ODC biphasic response. The RLW increase was similar to the response in intact mirex-dosed rats with a maximum 80% increase at 72 h postmirex dose.

The effects of love canal soil extracts on maternal health and fetal development in rats

The effects of a solvent extract of the surface soil of the Love Canal chemical dump site, Niagara Falls, New York, and of a natural extract, or leachate, which is drained from the canal for treatment, on the maternal health and fetal development were determined in rats. The solvent extract, which was contaminated with 2,3,7,8-tetrachlorodibenzo- p-dioxin (2,3,7,8-TCDD) at 170 ppb and numerous other chlorinated organic compounds with the primary identified components being the isomers of benzenehexachloride (BHC), was dissolved in corn oil and administered by gavage to pregnant rats at 0, 25, 75, or 150 mg crude extract/kg/day on Days 6–15 of gestation. A 67% mortality was observed at the highest dose. The rats were sacrificed on Day 20. Dose-related increases in relative liver weight accompanied by hepatocyte hypertrophy were observed at all dose levels. Fetal birthweight was decreased at 75 and 150 mg extract/kg/day. No major treatment-related soft tissue or skeletal malformations, except for delayed ossification, were observed. Based on literature values for BHC, all of the observed toxicity could be accounted for by the BHC contaminants of the extract. The crude organic phase of the leachate was administered to pregnant rats at 0, 10, 100, or 250 mg/kg/day as described above. Maternal weight gain decreased at 100 and 250 mg/kg/day, accompanied by 5 and 14% maternal mortality, and 1 and 3 dead fetuses, respectively. Early resorptions and the percentage of dead implants increased whereas fetal birthweights were decreased at 250 mg/kg/day. No major treatment-related soft tissue or skeletal malformations, except for delayed ossification, were observed. The primary components of the complex leachate by mass were tetrachloroethanes; however, 2,3,7,8-TCDD, which was present at 3 ppm, probably accounted for all the observed toxicity.

8 Final Report on the Safety Assessment of Drometrizole

Drometrizole is used in cosmetics as an ultraviolet (UV) light absorber and stabilizer, primarily at concentrations below 0.1%. Drometrizole is appreciably absorbed and metabolized. Repeated oral administration of Drometrizole for 14 or 28 days caused a significant increase in relative liver weight but did not affect the body weight gain. Drometrizole was relatively nontoxic in acute oral and dermal studies and only moderately irritating after direct instillation into the rabbit eye. Drometrizole was not mutagenic in either the Ames test with Salmonella typhimurium or in the mouse bone marrow micronucleus test. In clinical studies, Drometrizole tested at 1% was nonirritating in a single insult patch test. Twice daily applications of Drometrizole for 8 weeks produced no irritation. Only two hypersensitivity reactions were observed in a separate clinical study involving 145 patients. Cosmetic products containing up to 1.0% Drometrizole produced no irritation, sensitization, photosensitization, or phototoxicity. It is concluded that a 90-day subchronic oral toxicity study and mutagenicity testing in two systems other than the Ames assay and the mouse bone marrow micronucleus test are needed before an adequate safety assessment can be made. On the basis of the available data included in the report, it cannot be concluded that Drometrizole is safe for use in cosmetic products until such time that the appropriate safety data have been obtained and evaluated.

The effect of α-hexachlorocyclohexane on liver growth in intact and adrenalectomized rats

α-Hexachlorocyclohexane was administered as a single oral dose (100 mg/kg body wt) to both intact and adrenalectomized male Sprague-Dawley rats. In the intact rats there was a peak in [ 3H]thymidine incorporation into DNA at 30 hr and an increase in relative liver weight (liver weight/body wt × 100) which peaked at 60 hr post α-HCH dose. However, in α-HCH-dosed adrenalectomized rats [ 3H]thymidine incorporation into DNA remained elevated throughout the study period and relative liver weight was not significantly increased. In corticosterone-supplemented α-HCH-dosed Adx rats, [ 3H]thymidine incorporation into DNA was significantly reduced and RLW was increased comparable to that seen in intact animals. These results suggest that α-HCH-induced liver growth is mediated by corticosterone.

Toxicological studies on sophorolipid derivatives. (II). Subacute toxicity study of polyoxypropylene (12) [2'-0-beta-D-glucopyranosyl-beta-D-glucopyranosyl) oxy-] fatty acid ester-

Five groups of 12 male and 12 female rats each were fed diets containing 0, 0.06, 0.25, 1.00 and 4.00% PSL for a period of one month. Food consumption of PSL-fed groups did not differ from that of control. Urinalysis and autopsy findings were within normal in every group of rats treated. With 4.00% in the diet, body weight gain was significantly retarded and water consumption was increased, and soft stool occurred. In the hematological examination, decrease of red blood cells and increase of white blood cells were observed at the levels of 1.00 and 4.00% PSL. Changes of white blood cell differentials were also seen at the same levels. Serum Na+ concentration was slightly decreased at the 0.25, 1.00, 4.00% levels and serum glucose was also decreased at the 1.00, 4.00% levels, but the values were within the normal limits. Significant increase of relative liver weight, without histopathological changes, was observed at the 4.00% level. Histopathological examination revealed slight erosion, necrosis or intestinitis in small intestine, at the levels of 0.25, 1.00, 4.00% PSL. It was considered that these findings were attributed to the irritation potential of PSL or its metabolite. These results indicated that the non-effect level was 0.06% (53 mg/kg/day) and the level causing no toxicological effect was 0.25% (208 mg/kg/day), but no deleterious effects was observed in the levels greater than 0.25%.

Effects of repeated intravenous infusions of the plasticizer di-(2-ethylhexyl) phthalate in young male rats.

The effects of six iv infusions of an emulsion containing the plasticizer di(2-ethylhexyl) phthalate (DEHP) on the liver and testes were investigated in 40-day-old rats. Groups of five to six animals received the emulsion every other day in doses of 0, 5, 50 or 500 mg DEHP/kg body weight. Liver effects were studied by histological examination and by measuring bromosulfophthalein clearance, peroxisomal proliferation and certain enzymes in serum. Testicular effects were evaluated by light and electron microscopy. To investigate the possibility of an age-related effect on the testis, five 25-day-old rats were given six infusions of 500 mg DEHP/kg. Compared with control animals, the high-dose group showed a 36% increase in relative liver weight and a 41% increase in the number of peroxisomes. In Epon-embedded testicular material from animals given the highest dose, which is about 100 times the highest estimated human exposure, some altered Sertoli cells and some degenerated primary spermatocytes were observed. No age-related effect on the testis similar to that found following oral administration of DEHP was observed in this study.

Effects of dietary R-goitrin on hepatic and intestinal glutathione S-transferase, microsomal epoxide hydratase and ethoxycoumarin O-deethylase activities in the rat

The influence of dietary R-goitrin on components of the xenobiotic-metabolizing system was examined in the liver and small intestine of male Sprague-Dawley rats. Given at a level of 200 ppm in the diet for 14 days, the R-goitrin caused a statistically significant ( P < 0.05) 21% increase in liver weight relative to body weight. A less pronounced, but statistically significant, 11% increase in relative liver weight resulted from the administration of R-goitrin at 40 ppm in the diet. Hepatic glutathione S-transferase (GST) activity was significantly increased 1.5- and 2-fold over the basal level at concentrations of 40 and 200 ppm R-goitrin, respectively. Hepatic microsomal epoxide hydratase (EH) activity was also significantly increased. Hepatic EH activity was 1.6- and 3.3-fold greater in the 40- and 200-ppm R-goitrin groups, respectively, than in the control group given the basal diet. R-Goitrin at 200 ppm in the diet produced significant 1.2- and 1.4-fold increases of GST and microsomal EH activities, respectively, in the mucosa of the small intestine. The administration of R-goitrin at 40 or 200 ppm in the diet had no significant effect on either hepatic or intestinal ethoxycoumarin O-deethylase activity.

Effects of phenobarbitone and β-naphthoflavone on hepatic microsomal drug metabolising enzymes of the male beagle dog

Hepatic microsomes, prepared from male beagle dogs treated with phenobarbitone or β-naphthoflavone, were compared with microsomes from control dogs and from control, phenobarbitone and β-naphthoflavone treated rats with respect to various microsomal enzyme activities and for protein profiles generated on sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). The concentration of total cytochrome P-450 (0.46 nmoles/mg protein) and aldrin epoxidase (0.44 nmoles/mg/min) was lower in control dogs than in the rat, although ethoxycoumarin O-deethylase (ECOD-1.03 nmoles/mg/min) was 2 times and ethoxyresorufin O-deethylase (EROD-O.10 nmoles/mg/min) 5 times higher in the control dogs examined. Possibly as a result of this difference, β-naphthoflavone induced ECOD 10-fold and EROD 100-fold in the rat, while these enzymes were only increased 3-fold and 5-fold respectively in the two β-naphthoflavone-treated dogs. Consistent with this, control dog microsomes were found to contain a 58,000 mol. wt protein band that was not present in the SDS-PAGE of control rat microsomes but which was induced in both species by β-naphthoflavone. Although not identical, the effects of each inducer on the protein profiles were similar in both species, β-Naphthoflavone produced a marked increase in relative liver weight and, in contrast to published work in the rat, also increased NADPH-cytochrome c reductase levels in the dog. In general, the effects of phenobarbitone were qualitatively and quantitatively similar in both the dog and the rat.

A comparison of mirex-induced liver growth to liver regeneration

In intact rats given a single oral dose of mirex there was a dose-dependent increase in liver weight which peaked at 4 days. There were increases in hepatic RNA and protein, but DNA content per liver and DNA synthesis as measured by [ 3H]thymidine incorporation were unchanged. In partially hepatectomized rats dosed with mirex 24 h post-surgery, there was a dose-dependent increase in relative liver weight which peaked at 5 days. In partially hepatectomized rats simultaneously dosed with mirex, [ 3H]thymidine incorporation into DNA was unaltered. However, in rats dosed with mirex 24 h prior to partial hepatectomy, there was a 50% reduction in [ 3H]thymidine incorporation into hepatic DNA.

Mirex-induced adaptive liver growth: a corticosterone-mediated response.

The adaptive liver growth response was investigated in intact and adrenalectomized rats. When adult male rats were given a single oral dose of mirex (100 mg/kg body weight) there was a 72% increase in relative liver weight (RLW) in 72 hr. Based on [3H]-thymidine [( 3H]TdR) incorporation into hepatic DNA, there was also a wave of DNA synthesis which peaked at 48 hr and decreased to essentially control values by 96 hr post mirex dose. In mirex-dosed adrenalectomised (Adx) animals, the RLW was increased by only 38% and there was sustained DNA synthesis. When mirex-dosed Adx rats were given corticosterone supplements, the RLW response was similar to the RLW response in intact mirex-dosed rats. However, the 48-hr DNA synthesis peak seen in intact mirex-dosed rats was eliminated. From these data it is suggested that mirex-induced adaptive liver growth has two components: a hypertrophic component which is mediated by corticosterone, and a hyperplastic component which is independent of corticosterone.

Subchronic Feeding Study of N,N-Dimethylformamide in Rats and Mice

Wistar rats (25/ sex • group) and CD-1 mice (30/sex • group) were fed either a control diet or diet supplemented with N,N-dimethylformamide at the levels of 215, 750, and 2500 ppm for rats and 160,540, and 1850 ppm for mice. The duration of feeding was 104 days for rats and 119 days for mice. Body weight gain, food consumption, hematological and clinical chemical data, ophthalmic, gross, and microscopic examinations were used to study possible toxic or pathologic effects. A significant reduction in body weight gain was noted for male and female rats at the high dosage level. Food consumption in male rats at the high-dosage level and female rats at both the middle- and high-dosage levels was decreased. A significant dose-related increase in relative liver weights was noted in male and female rats. Absolute liver weights of male rats were comparable among groups, however, a dose-related increase was noted in female rats. No significant differences among groups were noted in body weight and food consumption data for mice. A significant dose-related increase in relative and absolute liver weights was noted in male and female mice. Histopathological evaluation revealed no evidence of a toxic effect related to feeding of N.N-dimethylformamide to Wistar rats and CD-1 mice. The increase in liver weight is considered to be a normal phenomenon (physiological adaptation) required for the biotransformation of N,N-dimethylformamide. The lack of hepatotoxicity in the present study may be the result of feeding N,N-dimethylf ormamide over waking hours versus bolus dosing (in other studies) in which hepatotoxicity was noted.

Modification by phenobarbital of chlorphentermine-induced changes in lung morphology and drug-metabolizing enzymes in newborn rats.

Treatment of newborn rat pups with 60 mg/kg.d chlorphentermine for 7 d produced on accumulation of alveolar foam cells accompanied by an increase in relative pulmonary tissue weight. In contrast, administration of 20 mg/kg.d for 1 wk did not markedly alter lung ultrastructure or weight in newborns. Both doses of chlorphentermine elevated the activity of pulmonary aminopyrine N-demethylase but not that of aniline hydroxylase. The increase in relative liver weight was associated with stimulation of the activities of aniline hydroxylase and aminopyrine N-demethylase in newborns administered either chlorphentermine dose. Phenobarbital treatment produced an increase in relative liver weight accompanied by elevated activities of pulmonary aminopyrine N-demethylase and hepatic aniline hydroxylase and aminopyrine N-demethylase. Simultaneous barbiturate and chlorphentermine administration produced stimulation in liver enzymes to the same extent as phenobarbital alone. In contrast, phenobarbital potentiated the chlorphentermine-induced rise in pulmonary aminopyrine N-demethylase. In the case of 60 mg/kg chlorphentermine and barbiturate, the observed potentiation of lung enzyme activity was associated with a reduction in the number of alveolar foam cells. The results suggest that chlorphentermine and phenobarbital stimulate drug-metabolizing enzyme in lung and liver of newborn rats and that phenobarbital may provide protection against phospholipidosis through stimulation of pulmonary, drug-metabolizing enzymes.

Studies of the effect of 2-(2′-hydroxy-5′-methylphenyl)benzotriazole on rat liver

The repeated oral administration of 2-(2′-hydroxy-5′-methylphenyl)benzotriazole, an ultraviolet-light absorber, in a dose of 300 mg/kg daily to young adult male rats for 14 or 28 days caused a reversible increase in relative liver weight. Microsomal glucuronosyltransferase activity was enhanced, whereas the activities of other drug-metabolizing enzymes, of glucose-6-phosphatase and of some lysosomal acid hydrolases were only marginally stimulated or remained essentially unchanged. Electronmicroscopic examination did not reveal any conspicuous proliferative response of the smooth endoplasmic reticulum in hepatocytes from the treated animals. After administration of a single oral 10-mg/kg dose of the test compound labelled with carbon-14, the radioactivity was almost completely eliminated from the body within 168 hr.

The effects of 1,1-di( p-chlorophenyl)-2-chloroethylene on plasma enzymes and blood constituents in the Japanese quail

Glutamate oxaloacetate transminase (GOT), glutamate dehydrogenase (GDH), sorbitol dehydrogenase (SDH), pseudo-cholinesterase (ChE) and various blood constituents were measured in the plasma of Japanese quail fed 1,1-di(p-chlorophenyl)-2-chloroethylene (DDMU) at low levels for periods ranging from 2 to 32 days. Previous work has shown that DDMU is a potent inducer of hepatic microsomal enzymes causing marked structural changes in the liver. A rapid increase in plasma GOT was observed within 4 days accompanied by an increase in relative liver weight. Plasma GDH and SDH increased to a maximum between 16 and 24 dyas which seems to be associated with hepatic cell proliferation. Plasma ChE showed a steady increase over the time course of DDMU administration. The level of plasma lipid was reduced after 4 days whereas the hepatic lipid content was substantially increased suggesting that the fatty liver condition may be caused by decreased release of triglyceride from the liver. Plasma glucose was reduced at 8 days but there was no evidence of a hyperglycaemic state. The changes noted after 2 days of DDMU diet were confirmed by measurements on birds 18 h after oral dosing the DDMU. The study demonstrates the value of plasma enzyme measurements for the early detection of toxic effects and indicates that DDMU administration leads to extrahepatic effects in addition to those previously described in the liver.

Effet du benzoate d'oestradiol sur la fonction hépatique et sur le métabolisme du cholesterol et des acides biliaires chez la caille

Immature female quails were treated for 6 days with estradiol benzoate at daily 0.01-, 0.02-, 0.01-, and 1-mg dosages. At the end of treatment, bile outflow, biliary cholesterol (CST), and bile acid (BA) secretory rates and liver, bile, and serum CST and BA levels were determined. Some quails were used to measure the ratio (R) of the rates of intravenously injected [2-14C]acetate radioactivity incorporation in cholic (C) and chenodeoxycholic (CDC) acids excreted in bile. The oestrogenic treatments at doses greater than 0.01 mg/day caused a marked disturbance in hepatic function and in CST and BA metabolism: they induced an increase in relative liver weight, liver CST stores, serum CST, C, CDC, and SGOT levels and in choleresis (respectively up to 56, 57, 650, 6000, 700, 42, and 235% increase at the daily 0.1-mg dosage) and they decreased bile total BA and CDC levels, bile and serum CDC to C level ratios, and R ratio (by 71, 82, 69, 84, and 58%, respectively). An increase in the bile salts independent fraction of bile was responsible for hypercholeresis, whether alone at low dosage or in conjunction with other factors at higher dosage. These results are compared with those obtained in mammals, particularly in the rat.

Enhanced hepatotoxicity of dimethylnitrosamine by pretreatment of rats with the antioxidant ethoxyquin

Pretreatment with a single oral dose of ethoxyquin (EMQ) (500 mg/kg) given 48 hr before dimethylnitrosamine (DMNA) and pretreatment with dietary doses (0.015% w/v) were found to enhance the elevated plasma glutamic oxaloacetic transaminase (GOT) activity induced by the ip administration of DMNA (30 mg/kg) to male rats. The increased hepatotoxicity of DMNA was confirmed by histologic evaluation. Pretreatment with EMQ caused increases in relative liver weights. These increases were reduced when DMNA was given 24 hr before measurements. Protein and cytochrome P-450 concentrations in liver were reduced by EMQ pretreatment. The observed inhibiting effect of DMNA on protein and cytochrome P-450 concentrations of rats that had received no pretreatment could not be measured following EMQ pretreatment. Concentrations of EMQ in liver and plasma varied in the range 0.2 to 1.7 ppm. Eighty to ninety-five percent of EMQ measured fluorimetrically was unchanged EMQ as determined by gas chromatography-mass spectrometry. No correlation was found to exist between the grade of necrosis and the EMQ concentration in liver and plasma. However, correlation seemed to exist between enhancement of DMNA-induced toxicity and stimulation of liver growth. It was suggested that EMQ-induced growth of some hepatic systems was not related to cytochrome P-450, and that this induction mechanism led to an increased hepatotoxicity of DMNA.

STUDIES ON THE LIVER ENLARGEMENT INDUCED BY DIETARY ADMINISTRATION OF DI-(2-ETHYLHEXYL) PHTHALATE (DEHP).

Di-(2-ethylhexyl) phthalate (DEHP) was mixed into diet and given to Wistar male rats for 16 days. A significant and dose-dependent increase in the relative liver weight (RLW) was observed in the rats fed DEHP at dietary levels greater than 0.1%. The RLW increased progressively with the duration of the treatment, reaching its maximun in two weeks. Biochemical analysis of the principal hepatic components has shown that the increase in RLW induced by DEHP was due to an increase in the total amounts of protein, water, lipid, and nucleic acids. The increase in protein was most marked and was due mainly to the increase in non-collagen protein. The total amounts of glycogen and collagen did not change. However, most of these components were found to be unchanged or reduced in their contents per liver weight, except that of protein. The increase in RLW is caused equally by the increase in cell number and in the cell volume, the nuclear DNA content being unaffected. The content of cytochrome P-450 in microsomes increased in the rats of both sex fed a 0.5% DEHP-diet for 16 days. However, the activities per mg of microsomal protein or per g of liver of aminopyrine N-demethylase and aniline hydroxylase decreased in male rats but increased in female rats. Total activities of these enzymes increased markedly in both sex of animals. Glucose 6-phosphatase, acid phosphatase and cytochrome c oxidase were reduced significantly in their activities per liver weight but glucose 6-phosphate dehydrogenase was unchanged. The significance of the liver enlargement induced by DEHP is discussed in relation to the physiological response of liver and to possible pathological changes of liver.

Short-term toxicity of 1-naphthaleneacetic acid in rats

In a 90-day feeding study, 4 groups of 10 male and 10 female rats received in the diet 0, 200, 1000 and 5000 ppm 1-naphthaleneacetic acid (1-NAA). Growth and food intake was reduced significantly only in males on 5000 ppm. Haematological examination yielded essentially negative results except for a non-significant reduction at the 1000 and 5000 ppm levels in the leucocyte count, mainly due to a reduction in neutrophils. No significant effects were observed in the renal concentration test, urinalysis, renal histochemistry or histology of a wide range of organs at any level of 1-NAA tested. Increased relative weights of thyroid, testes, brain and liver were confined to the 5000 ppm level. The increase in relative liver weight was not accompanied by histological liver damage and was associated with elevated liver microsomal enzyme activity. The loss of glucose 6-phosphate (G6Pase) and increase in glucose 6-phosphate dehydrogenase (G6PDH) seen histochemically in the centrilobular region of the liver in males on 5000 ppm, accompanied by glycogen depletion in the liver, could however be indicative of liver damage. On the basis of conventional criteria, a no-effect level of 1000 ppm would have been indicated by this study but in view of liver glycogen depletion at all levels tested a no-effect level was not established.

2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD): Results of a 13-week oral toxicity study in rats

Rats were given 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) at dosages of 0, 0.001, 0.01, 0.1, or 1.0 μg/kg, 5 days/wk for 13 wk. Doses of 1.0 μg TCDD/kg/day caused some mortality, inactivity, decreased body weights and food consumption, icterus, increased serum bilirubin and alkaline phosphatase, pathomorphologic changes in the liver, lymphoid depletion of the thymus and other lymphoid organs, increased urinary excretion of porphyrins and delta-aminolevulinic acid, and minimal alterations of some hematopoietic components. Morphological evidence of a functional suppression of the reproductive organs was consistent with either a direct toxic effect of this dose of TCDD, or an indirect toxic effect associated with the poor physical condition of these rats. Doses of 0.1 μg TCDD/kg/day caused decreased body weights and food consumption, and slight degrees of liver degeneration and lymphoid depletion. Other effects seen only in females given this dose level included increases in urinary excretion of coproporphyrin and delta-aminolevulinic acid and increases in serum alkaline phosphatase and bilirubin. Effects seen only in males given this dose level included a depression of some hematologic parameters (packed cell volume, red blood cells, and hemoglobin). In rats given 0.01 or 0.001 μg TCDD/kg/day, all parameters were essentially unaffected, except for a slight increase in the mean liver-to-body-weight ratio in rats given 0.01 μg TCDD/kg/day. This slight increase in relative liver weight was not considered of any toxicological significance. These data indicate that no discernible ill effects occurred in rats given 0.01 or 0.001 μg TCDD/kg 5 days/wk for 13 wk.

Microsomal drug-metabolizing enzyme activity in rats given α-(2,4-dichlorophenyl)-α-phenyl-5-pyrimidinemethanol for periods of 14 days to 2 years

The dose-response relationships for stimulation of hepatic drug-metabolizing enzymes were studied in rats given α-(2,4-dichlorophenyl)-α-phenyl-5-pyrimidinemethanol (EL-273) in the diet for periods of 2 weeks-2 years. The dietary concentrations ranged from 20 to 5000 ppm. p-Nitroanisole metabolism was not affected by EL-273 concentrations of 80 ppm or less. With dietary concentrations of 160–1250 ppm the rate of metabolism increased in proportion to the log of the dose. Concentrations greater than 1250 ppm produced no additional increase. Above a threshold of 80 ppm, EL-273 increased relative liver weight and microsomal protein. The effects of EL-273 on the liver at 2 weeks were reversible within 2 weeks on control diet. In chronic tests the increases in relative liver weight and p-nitroanisole metabolism reached maxima after 2 weeks of EL-273 administration and remained relatively constant throughout the remainder of the 2-year test.