Hepatic Mixed Function Oxidase Activity Research Articles

Propylene glycol monomethyl ether (PGME): inhalation toxicity and carcinogenicity in Fischer 344 rats and B6C3F1 mice.

A series of inhalation studies with propylene glycol monomethyl ether (PGME) vapor were undertaken to characterize its subchronic toxicity in mice and chronic toxicity/oncogenicity in rats and mice. Groups of male and female Fischer 344 rats and B6C3F1 mice were exposed to 0, 300, 1,000, or 3,000 ppm vapor from 1 week to 2 years. Primary treatment-related effects included: initial sedation of animals exposed to 3,000 ppm and its subsequent resolution correlating with induction of hepatic mixed function oxidase activity and S-phase DNA synthesis; elevated mortality in high-exposure male rats and mice (chronic study); elevated deposition of alpha2u-globulin (alpha2U-G) and associated nephropathy and S-phase DNA synthesis in male rat kidneys; accelerated atrophy of the adrenal gland X-zone in female mice (subchronic study only); and increased occurrence and/or severity of eosinophilic foci of altered hepatocytes in male rats. No toxicologically relevant statistically significant increases in neoplasia occurred in either species. A numerical increase in the incidence of kidney adenomas occurred in intermediate-exposure male rats; however, the association with alpha2U-G nephropathy, a male rat specific effect, indicated a lack of relevance for human risk assessment.

Assessing the biological status of fish in a river receiving pulp and paper mill effluents

This study compared the use of sentinel species- and community-based field approaches for assessing the biological status of fish living in a river receiving pulp and paper mill effluents. Three approaches were compared. Two approaches used sentinel species. One of these involved an internal/external examination of the fish that leads to the calculation of a fish health assessment index (HAI) and the other involved biochemical measurements of hepatic mixed function oxidase (MFO) activity and plasma steroid levels. The third approach characterized the fish community structure according to an index of biotic integrity (IBI). The comparison focused on how the methods respond to the hypothesis that recent process modifications/effluent treatment changes, resulting in demonstrable improvements in effluent quality, have beneficial effects on fish. Neither of the approaches using sentinel fish indicated clear mill-related influences either before or after the process modifications/effluent treatment changes. There was no evidence of depressed plasma steroids and increased MFO activity in fish frequently associated with mill effluent exposure in previous studies. While the HAI was higher at stations downstream from two mills, this could not be linked to effluent exposure alone. In contrast, the study of community structure showed a substantial improvement in fish assemblages at all the mill sites.

A study of the factors affecting the metabolic clearance of quinine in malaria

To assess the factors that contribute to impaired quinine clearance in acute falciparum malaria. Sixteen adult Thai patients with severe or moderately severe falciparum malaria were studied, and 12 were re-studied during convalescence. The clearance of quinine, dihydroquinine (an impurity comprising up to 10% of commercial quinine formulations), antipyrine (a measure of hepatic mixed-function oxidase activity), indocyanine green (ICG) (a measure of liver blood flow), and iothalamate (a measure of glomerular filtration rate) were measured simultaneously, and the relationship of these values to the biotransformation of quinine to the active metabolite 3-hydroxyquinine was assessed. During acute malaria infection, the systemic clearance of quinine, antipyrine and ICG and the biotransformation of quinine to 3-hydroxyquinine were all reduced significantly when compared with values during convalescence. Iothalamate clearance was not affected significantly and did not correlate with the clearance of any of the other compounds. The clearance of total and free quinine correlated significantly with antipyrine clearance (rs = 0.70, P = 0.005 and rs = 0.67, P = 0.013, respectively), but not with ICG clearance (rs = 0.39 and 0.43 respectively, P > 0.15). In a multiple regression model, antipyrine clearance and plasma protein binding accounted for 71% of the variance in total quinine clearance in acute malaria. The pharmacokinetic properties of dihydroquinine were generally similar to those of quinine, although dihydroquinine clearance was less affected by acute malaria. The mean ratio of quinine to 3-hydroxyquinine area under the plasma concentration-time curve (AUC) values in acute malaria was 12.03 compared with 6.92 during convalescence P = 0.01. The mean plasma protein binding of 3-hydroxyquinine was 46%, which was significantly lower than that of quinine (90.5%) or dihydroquinine (90.5%). The reduction in quinine clearance in acute malaria results predominantly from a disease-induced dysfunction in hepatic mixed-function oxidase activity (principally CYP 3A) which impairs the conversion of quinine to its major metabolite, 3-hydroxyquinine. The metabolite contributes approximately 5% of the antimalarial activity of the parent compound in malaria, but up to 10% during convalescence.

Mixed‐function oxidase enzyme activity and oxidative stress in lake trout (Salvelinus namaycush) exposed to 3,3′,4,4′,5‐pentachlorobiphenyl (PCB‐126)

AbstractJuvenile lake trout were intraperitoneally injected with corn oil containing nominal concentrations of 0, 0.6, 6.3, or 25 μg [14C]‐3,3′,4,4′,5‐pentachlorobiphenyl (PCB‐126) per gram of body weight. The PCB‐126 accumulated in liver in a dose‐dependent manner to a sustained concentration by 6 weeks and remained elevated for the 30‐week experimental period. Mixed‐function oxidase (MFO) enzyme activity was elevated in the two highest dose groups relative to the control group, but not in the low‐dose group throughout the 30 weeks. Oxidative stress, measured by the thiobarbituric acid reactive substances test, was correlated with ethoxyresorufin O‐deethylase and was elevated in liver of the two highest PCB dose groups but not the low‐dose group. The activities of the enzymatic antioxidants superoxide dismutase, catalase, and glutathione peroxidase were unaffected by PCB‐126 exposure. The nonenzymatic antioxidant tocopherol was depleted to approximately 75% of the control concentration in liver of all three PCB‐dosed groups. Hepatic ascorbic acid levels were not different in any of the treatment groups. Retinol was depleted by greater than an order of magnitude in liver of the two highest dose groups but not in the low‐dose group. This study demonstrates a correlation between hepatic MFO activity and oxidative stress in PCB‐exposed lake trout. Tocopherol and retinol may be important mediators of oxidative stress but additional study is required to confirm the antioxidant activity of retinol.

13C]Aminopyrine breath test detects altered liver metabolism caused by low-dose oral contraceptives

The [13C]aminopyrine breath test measures hepatic mixed function oxidase activity. The cumulative percent dose recovered over 2 hr is a sensitive indicator of hepatic dysfunction; values < or = 7.0% have been shown to indicate severe liver disease. Previous studies have suggested that the test results may be influenced by the use of oral contraceptives steroids. We compared the results from five non-oral contraceptive-using women with those from 31 women whose duration of oral contraceptive steroid usage ranged from 4 to 204 months. The women were taking one of four oral contraceptive formulations that differed in the amounts of estrogen (20, 35, or 50 micrograms with 1 mg progesterone) and progesterone (35 micrograms estrogen with stepped levels of progesterone of 0.5, 0.75, and 1.0 mg). The [13C]aminopyrine breath test was performed on days 21 and 28 of the menstrual cycle. Cumulative percent dose recovery values among the normal menstrual cycle of non-oral contraceptive steroid-using women were 12.1 +/- 1.6 and 11.8 +/- 1.5% (mean +/- SD). In contrast, oral contraceptive steroid users showed a marked reduction in cumulative percent dose recovery at 21 days, averaging 6.1 +/- 2.3% (P < 0.001), and returned to normal values (10.2 +/- 3.5%) at 28 days in most women(seven days after oral contraceptive steroid usage was paused). The adverse impact on hepatic mixed function oxidase by oral contraceptive formulations did not differ on the basis of estrogen or progesterone content. The adverse impact of oral contraceptive usage on the mixed function oxidase activity measured by the [13C]aminopyrine breath test must be considered for women of childbearing potential.

Downregulation of male-specific cytochrome P450s 2C11 and 3A2 in bile duct-ligated male rats: Importance to reduced hepatic content of cytochrome P450 in cholestasis

The effects of bile duct ligation (BDL) on the activity and content of individual hepatic mixed-function oxidases (MFOs) was examined. Five days after BDL, hepatic microsomal total cytochrome P450 (CYP) content and NADPH-cytochrome P450-reductase (P450-reductase) activity were reduced to 56% and 57% of control, respectively. MFO activities attributable to the sexually undifferentiated CYPs 1A, 2A1, 2C6, and 2E1 were decreased to 32% to 52% of control, but the activities of two male sex-specific CYPs, 2C11 and 3A2, were reduced to a significantly greater extent (P < .05). The microsomal contents of CYP proteins 2C6 and 2E1 were decreased after BDL to 61% and 63% of control, whereas 2C11 and 3A2 proteins were 21% and 45% of control. Corresponding reductions of the messenger RNA (mRNA) species for CYP 2C11 (9% of control) and 3A2 (37%) were detected, whereas there was no reduction of 2C6 mRNA. These findings are consistent with downregulation of the CYP 2C11 and 3A2 genes. Nuclear run-on studies performed 3 days after BDL showed that there was a generalized impairment of gene transcription after BDL, but a disproportionate reduction in transcription of CYPs 2C11 and 3A2. A possible explanation for downregulation of CYP 2C11 and 3A2 was provided by the observation that serum estradiol concentrations were threefold greater in BDL male rats, while serum testosterone was reduced; estradiol is known to downregulate CYPs 2C11 and 3A2. It is concluded that male sex-specific CYP enzymes are decreased to a greater extent than other microsomal proteins in BDL male rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Downregulation of male-specific cytochrome P450s 2C11 and 3A2 in bile duct-ligated male rats: Importance to reduced hepatic content of cytochrome P450 in cholestasis

The effects of bile duct ligation (BDL) on the activity and content of individual hepatic mixed-function oxidases (MFOs) was examined. Five days after BDL, hepatic microsomal total cytochrome P450 (CYP) content and NADPH-cytochrome P450-reductase (P450-reductase) activity were reduced to 56% and 57% of control, respectively. MFO activities attributable to the sexually undifferentiated CYPs 1A, 2A1, 2C6, and 2E1 were decreased to 32% to 52% of control, but the activities of two male sex-specific CYPs, 2C11 and 3A2, were reduced to a significantly greater extent ( P < .05). The microsomal contents of CYP proteins 2C6 and 2E1 were decreased after BDL to 61% and 63% of control, whereas 2C11 and 3A2 proteins were 21% and 45% of control. Corresponding reductions of the messenger RNA (mRNA) species for CYP 2C11 (9% of control) and 3A2 (37%) were detected, whereas there was no reduction of 2C6 mRNA. These findings are consistent with downregulation of the CYP 2C11 and 3A2 genes. Nuclear run-on studies performed 3 days after BDL showed that there was a generalized impairment of gene transcription after BDL, but a disproportionate reduction in transcription of CYPs 2C11 and 3A2. A possible explanation for downregulation of CYP 2C11 and 3A2 was provided by the observation that serum estradiol concentrations were threefold greater in BDL male rats, while serum testosterone was reduced; estradiol is known to downregulate CYPs 2C11 and 3A2. It is concluded that male sex-specific CYP enzymes are decreased to a greater extent than other microsomal proteins in BDL male rats. It is proposed that the reduced activity of steroid metabolizing enzymes, which occurs after BDL, results in altered serum sex steroid concentrations, which, in turn, lead to decreased transcription of CYP 2C11 and 3A2 genes.

Short-term inhalation toxicity of methanol, gasoline, and methanol/gasoline in the rat.

Four- to five-week-old male and female Sprague Dawley rats were exposed to vapors of methanol (2500 ppm), gasoline (3200 ppm), and methanol/gasoline (2500/3200 ppm, 570/3200 ppm) six hours per day, five days per week for four weeks. Control animals were exposed to filtered room air only. Depression in body weight gain and reduced food consumption were observed in male rats, and increased relative liver weight was detected in rats of both sexes exposed to gasoline or methanol/gasoline mixtures. Rats of both sexes exposed to methanol/gasoline mixtures had increased relative kidney weight and females exposed to gasoline and methanol/gasoline mixtures had increased kidney weight. Decreased serum glucose and cholesterol were detected in male rats exposed to gasoline and methanol/gasoline mixtures. Decreased hemoglobin was observed in females inhaling vapors of gasoline and methanol/gasoline at 570/3200 ppm. Urine from rats inhaling gasoline or methanol/gasoline mixtures had up to a fourfold increase in hippuric acid, a biomarker of exposure to the toluene constituent of gasoline, and up to a sixfold elevation in ascorbic acid, a noninvasive biomarker of hepatic response. Hepatic mixed-function oxidase (aniline hydroxylase, aminopyrine N-demethylase and ethoxyresorufin O-deethylase) activities and UDP-glucuronosyltransferase activity were elevated in rats exposed to gasoline and methanol/gasoline mixtures. Histopathological changes were confined to very mild changes in the nasal passages and in the uterus, where decreased incidence or absence of mucosal and myometrial eosinophilia was observed in females inhaling gasoline and methanol/gasoline at 570/3200 ppm. It was concluded that gasoline was largely responsible for the adverse effects, the most significant of which included depression in weight gain in the males, increased liver weight and hepatic microsomal enzyme activities in both sexes, and suppression of uterine eosinophilia. No apparent interactive effects between methanol and gasoline were observed.

A laboratory exposure procedure for screening pulp and paper mill effluents for the potential of causing increased mixed function oxidase activity in fish

To better understand the relationships between pulp manufacturing processes and mixed function oxidase (MFO) enzyme induction in fish, a practical and standardized exposure procedure is required. This study was undertaken to develop a laboratory-based exposure procedure to quantify the relative MFO induction potencies of different types of pulp and paper mill effluents. One major consideration in developing the procedure was to ensure that the protocol was practical so that tests could be performed in a short time, with small volumes of effluents and using simple experimental conditions. A series of concentration-response and time-course experiments were conducted to find the minimum time and effluent concentration which could distinguish the ability of different effluents to cause significant MFO induction in rainbow trout in the laboratory. Experiments were also conducted to determine the effects of biotic and abiotic factors such as loading density, fish size and feeding regime. This study showed that the exposure of rainbow trout in the laboratory to 10% concentration of secondary-treated effluent for 96 h caused significant increases in hepatic MFO activity. The magnitude of MFO induction was comparable to other field and laboratory observations. While fish size, loading density and feeding regime were found to affect the test results, consistent responses within a laboratory using this protocol are possible, provided that these factors are standardized. Therefore, the short-term exposure approach described in this paper could be a relevant tool for assessing the ability of different types of pulp and paper mill effluents to cause MFO induction in fish.

Cadmium-induced sexual dysfunction does not involve increased hepatic metabolism of testosterone nor increased circulating levels of corticosterone

Sexually experienced male rats were injected IP with 0, 0.3, 1.5, 3.0, or 6.0 mg/kg cadmium chloride. The highest dose was fatal within 48 h of injection. A dose-related deficit in erectile function was observed in ex copula tests 48 h after injection. Copulatory dysfunction was evident in mating tests 72 h after injection. Hepatic mixed function oxidase activity after 0.3 mg/kg injections was not different from controls, but was diminished by 50% in rats treated with 3.0 mg/kg. The higher cadmium doses (1.5 and 3.0 mg/kg) were associated with equivalent and marked reductions in circulating testosterone levels, and lesser decrements in circulating corticosterone levels. The rats treated with 1.5 or 3.0 mg/kg cadmium chloride lost weight (32 ± 12 and 39 ± 9 g, respectively). Relative decapsulated adrenal gland weights were markedly increased in rats treated with 3.0 mg/kg. These data indicate that exposure to cadmium is associated with alterations in sexual, hepatic, and adrenal function, with erectile dysfunction occurring at the lowest dose. The effects on copulatory behavior are especially striking because it requires some weeks for copulatory behavior to wane following castration.

Biomonitoring of pollution: the hepatic cytochrome P-450 enzyme system in the feral mouse Apodemus flavicollis as indicator

The aim of the present study was to find a suitable wild-rodent to be used as terrestrial bioindicator. The wild mice were trapped at three sites around Vienna and at a fourth location in the countryside. Apodemus flavicollis, the yellow-necked mouse, was the most frequently captured mouse at all four sites. For each sample hepatic microsomal protein content, cytochromes b5 and P450, and enzyme catalytic activities-ECOD, EROD, BROD and PROD were measured. Except for one male urban group no significant differences between rural and urban groups in ECOD activity were observed. Increased cytochrome b5 and P450 contents per mg of microsomal protein were found in one of the male and all the three female urban groups. However the alkoxyresorufin O-dealkylase activities were significantly increased in both sexes of the three city groups. These results suggest that induction of cytochrome P450IA and P450IIB families has occurred in urban populations, indicating a possible pollution with halogenated dioxins and furans, PCBs, PAHs etc. The data show that induction of hepatic mixed function oxidase (HMFO) activity in the feral mouse Apodemus flavicollis can be successfully used as a terrestrial bioindicator for pollution monitoring.

Effects of Dietary Fat and Protein Sources on Performance, Lipid Content and Mixed Function Oxidase in Liver, and Fat Deposition and Adipocyte Cellularity in Abdomen in Broiler Chickens.

Abdominal fat deposition and the cellularity, and lipid content and mixed function oxidase (MFO) activity in livers were studied in broiler chickens fed isoenergetic and isonitrogenous diets which were different in the fat and protein sources.Feeding corn oil (CO) or chicken oil (CH) tended to decrease abdominal fat content compared with feeding yellow grease (YG) at 56 days of age, although no significant differences were observed in general performance. In female chickens, the decrease in the abdominal fat pad was associated with decrease in the adipocyte volume. At 21 days of age, lipid and triglyceride contents in the liver of chickens fed CO or CH were numerically lower than those in YG-fed chicks, and hepatic MFO activity was elevated by feeding CO.Feeding high fat diet (HF) increased liver triglyceride content at 21 days and tended to increase abdominal fat content at 56 days of age. Feeding fish meal (FM) as a major protein source increased the abdominal fat content in comparison with feeding soybean meal+fish meal (SFM), irrespective of dietary fat content, at 21 days of age. In chickens fed low fat diet (LF) for 21 days, FM decreased lipid and triglyceride contents in the liver and the decrease was associated with an activation of the hepatic MFO activity.

Pathophysiology of fescue toxicosis

The pathophysiology of fescue toxicosis is discussed relative to observed symptoms and the inhibition of animal production (average daily gain and decreased reproductive efficiency). Hyperthermia, vasoconstriction and perhaps increased activity of hepatic mixed-function oxidases are important effects. Perhaps secondarily intake is reduced by the above mechanisms and possibly by unpalatability factors. The decreased milk yield is considered a function of decreased intake and suppressed prolactin secretion. Evidence is discussed that corpora lutea in cattle are morphologically altered and consequently may not support a pregnancy. The effect of endophyte presence upon the outcome of pregnancy in the mare is considered a function of an alteration in placental function as a result of vasoconstriction.

Elimination of PCB congeners via milk in rabbits administered Fenclor 64.

A single dose of 100 mg per kg body weight of a commercial mixture of polychlorinated biphenyls (PCB), Fenclor 64 was given intraperitoneally to pregnant rabbits. The distribution in dams and foetuses and excretion in milk was investigated for six of the congeners by quantifying them in fat from maternal adipose tissue, from whole foetuses and newborn bodies and from newborn gastric contents. The cytochrome-P-450 induction after Fenclor 64 in foetuses and suckling off-spring was followed by measuring the following hepatic mixed function oxidase (MFO) activities: p-nitroanisole-demethylase, ethoxyresorufin-deethylase, ethoxycoumarin-deethylase and NADPH cytochrome-C reductase. At the 28th day of pregnancy PCB fat concentrations in foetuses were similar to those in mothers (126.4 +/- 7.1 and 152.6 +/- 28.1 micrograms/g of fat, respectively). By the 5th day of life fat concentrations in the youngs were double those of foetuses (216.81 +/- 8.12 micrograms/g) and remained high until weaning (142.2 +/- 15.5 micrograms/g at the 20th day). PCB concentrations in mothers' fat decreased during lactation (104.1 micrograms/g at the 20th day) but at the end of the experiment they were still high (95.5 micrograms/g). The cytochrome-P-450 concentration and MFO activities in young rabbits' livers from treated dams were significantly higher than controls from the 5th (P less than 0.01) to the 10th (P less than 0.01) day of life, with the exception of NADPH-cyt-C-reductase (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute toxicity, percutaneous absorption and effects on hepatic mixed function oxidase activities of 2,4,4'-trichloro-2'-hydroxydiphenyl ether (Irgasan DP300) and its chlorinated derivatives.

Acute toxicity of 2,4,4'-trichloro-2'-hydroxydiphenyl ether (Irgasan DP300) (I) and its three chlorinated derivatives, 2',3,4,4'-tetrachloro-2-hydroxydiphenyl ether (II), 2',4,4',5-tetrachloro-2-hydroxydiphenyl ether (III) and 2',3,4,4',5-pentachloro-2-hydroxydiphenyl ether (IV), in mice were examined by intraperitoneal injection. The LD50 values of Irgasan DP300, II, III and IV were 1,090, 710, 650 and 430 mg/kg, respectively. The percutaneous absorptions of these tritiated compounds were also examined by the application on the backs of mice. The radioactivities in most tissues reached to the maximal levels at 12 h or 18 h after dosing, which corresponded to 11-76% of the maximal levels given by the oral administration (Kanetoshi et al. 1988a). These results show the high percutaneous absorbability of Irgasan DP300 and its chlorinated derivatives. The intraperitoneal administrations of III and IV to rats induced hepatic microsomal aminopyrine N-demethylase and aniline 4-hydroxylase activities similarly to phenobarbital. These chlorinated derivatives also increased cytochrome P-450 content, and the activities of aminopyrine N-demethylase and N-methylaniline N-demethylase in hepatic microsomes from mice. The extents of the increases were similar to those by phenobarbital and 3-methylcholanthrene.

The modulation of hepatic mixed-function oxidase activity by insulinoma

The modulation of hepatic mixed-function oxidase activity by insulinoma

The effects of cobalt chloride, SKF-525A, and N-(3,5-dichlorophenyl)succinimide on in vivo hepatic mixed function oxidase activity as determined by single-sample plasma clearances.

1. Four drugs--antipyrine, theophylline, quinidine, and ethosuximide--were used as probes of in vivo hepatic mixed function oxidase (MFO) activity. Functional MFO activity was evaluated by estimating probe clearances subsequent to pretreatment of rats with either cobalt chloride, SKF-525A, or N-(3,5-dichlorophenyl) succiminide (NDPS). 2. Clearances of each probe were estimated from single plasma concentration measurements. Each pretreatment altered the clearances of this panel of probes in a different way. NDPS pretreatment increased theophylline clearance while slowing quinidine and ethosuximide clearances. SKF-525A slowed all probe clearances except for ethosuximide. Cobalt chloride slowed all probe clearances except for theophylline. 3. The use of multiple probes as substrates for the hepatic cytochrome P-450 system can provide some insight into the functional consequences of xenobiotic exposures on that system. Moreover, xenobiotic-induced functional changes on hepatic MFO when assessed in vivo appear to be modest relative to changes in in vitro activity or hepatic cytochrome P-450 content. This minimally invasive multiprobe method may be useful for assessing xenobiotic influences on human hepatic MFO in vivo.

Effects of arsenite on hepatic mixed-function oxidase activity in rats.

1. Injection of arsenite (As3+) to control rats results in losses of total hepatic cytochrome P-450 and significant decreases of ethoxycoumarin O-deethylase (ECOD) and ethoxyresorufin O-deethylase (EROD) activities. However, As3+ appears to decrease the activity of these enzymes differentially, with EROD showing greater sensitivity than ECOD. 2. Injection of As3+ to rats treated with phenobarbital and isosafrole significantly decreases the total content of hepatic cytochrome P-450 and various mixed function oxidase (MFO) activities, with the exception of ECOD which appears to be insensitive to As3+. 3. 3-Methylcholanthrene administration apparently protects against the effects of As3+ on the cytochrome P-450 system, since total content of the cytochrome P-450 and various MFO activities were all insensitive to this treatment.

Impact of Bleached Kraft Mill Effluent on Population Characteristics, Liver MFO Activity, and Serum Steroid Levels of a Lake Superior White Sucker (Catostomus commersoni) Population

White sucker (Catostomus commersoni) collected from a site receiving primary-treated bleached kraft mill effluent (BKME) were older and had a higher condition factor than fish at a reference site and grew more slowly than fish from three other areas of Lake Superior. The BKME-exposed fish also exhibited an increased age to maturity, smaller gonads, lower fecundity with age, an absence of secondary sex characteristics in males, and females failed to show an increase in egg size with age. Lower serum estradiol and testosterone concentrations and greater hepatic mixed-function oxidase (MFO) activity, as measured by conversion of diphenyloxazole and benzo[ajpyrene were also observed in the BKME-exposed fish. The level of MFO activity varied with season; differences could not be detected between sites during the spring spawning period, but were markedly elevated (up to ninefold) at the BKME site during the summer. The poorer performance of fish at the BKME site appears to be related to decreased levels of serum steroids and consequent abnormalities in reproductive development and carbohydrate metabolism, although the relationship of the changes in steroid levels with the increased hepatic enzyme activity remains to be established.

COMPARISON OF THE EFFECTS OF PIPERINE ADMINISTERED INTRAGASTRICALLY AND INTRAPERITONEALLY ON THE LIVER AND LIVER MIXED-FUNCTION OXIDASES IN RATS

Piperine, a major pungent constituent of black and red peppers, was administered to rats intragastrically and intraperitoneally to study whether it alters the activities of hepatic mixed-function oxidases (MFO) and serum enzymes as specific markers of hepatotoxicity. An intragastric dose of 100 mg/kg of piperine to adult, male Sprague-Dawley rats caused an increase in hepatic microsomal cytochrome P-450 and cytochrome b5, NADPH-cytochrome c reductase, benzphetamine N-demethylase, aminopyrine N-demethylase and aniline hydroxylase 24 h following treatment. On the other hand, a 10 mg/kg dose given i.p. exhibited no effect on the activities of the aforementioned parameters of the hepatic drug-metabolizing enzyme system. However, when the intragastric and intraperitoneal doses were increased to 800 mg/kg and 100 mg/kg, respectively, the black pepper alkaloid produced a significant decrease in the levels of cytochrome P-450, benzphetamine N-demethylase, aminopyrine N-demethylase and aniline hydroxylase 24 h after treatment. None of the treatments significantly elevated the activities of serum sorbitol dehydrogenase (SDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and isocitrate dehydrogenase (ICD), suggesting that piperine is not a hepatotoxic agent.