Behavioral effects following single and combined maternal exposure to PCB 77 (3,4,3',4'-tetrachlorobiphenyl) and PCB 47 (2,4,2',4'-tetrachlorobiphenyl) in rats

The present study has compared the neurobehavioral effects of two structurally different PCB congeners or their combination in rats. Time-mated Long-Evans rats received daily injections of the coplanar PCB 77 (3,4 3',4'-TCB: 0.5 or 1.5 mg/kg), the di-ortho-chlorinated PCB 47 (2,4,2',4'-TCB: 1.5 mg/kg) or a congener mixture (0.5 mg/kg PCB 77 + 1.0 mg/kg PCB 47) from day 7 to 18 of gestation. The PCB exposure levels in brain and perirenal fat of dams and offspring were determined by GC/ECD on gestational day 19 (GD 19), postnatal day 21 (PND 21), and PND 45. PCB 77 was accumulated to a smaller degree than PCB 47. On GD 19, PCB 77 was found to a greater extent in the brains of the offspring than in the brains of the dams, whereas the level of PCB 47 was almost the same in dams and offspring. The testing of open-field behavior in male rats on PND 18 and PND 70 revealed an altered distribution of activity with enhanced activity in the inner zone in PCB 77-treated rats compared to all other groups, while the overall activity was not changed. Distance traveled and rearing behavior on PND 340 were elevated relative to controls in all PCB-treated groups, indicating age-related effects of maternal exposure. A step-down passive avoidance task revealed decreased latencies in the PCB 77 and combined exposure groups on PND 80. Only PCB 77-treated animals showed increased latencies on PND 100 on the haloperidol-induced catalepsy test. These results indicate long-term effects of maternal exposure to PCB 77 on emotional and motor functions. At the dose levels used in the present experiments, the two congeners given in combination did not cause additive or synergistic effects. Instead, concurrent exposure to PCB 47 seemed to counteract PCB 77-induced changes in the pattern of activity.     

Effects of 3,4,3',4'-tetrachlorobiphenyl on thyroid function and histology in marmoset monkeys

Marmoset monkeys were treated with oral doses of 0.1, 1 or 3 mg 3,4,3',4'-tetrachlorobiphenyl (TCB) per kg body weight 2 times a week for 18-23 weeks. Histological examination of the thyroid gland revealed a dose-dependent follicular cell hyperplasia. The morphological changes were associated with various disturbances of thyroid function. The average serum thyroxine (T4) levels during the treatment period were reduced by more than 99% in monkeys receiving 3 mg TCB/kg, by 81% in marmosets on a dose of 1 mg TCB/kg, and by 35% with 0.1 mg TCB/kg. The reduction in serum T4 levels was established from the earliest time point (2 weeks) throughout the whole dosing period (18-23 weeks). The reduction in serum T4 levels was reflected in decreased free thyroxine (FT4) index in the 1 and 3 mg TCB/kg dose groups. Serum triiodothyronine (T3) levels were lowered in the 3 mg/kg dose group already after 2 weeks. Evidence for decreased binding to carrier proteins is suggested by increased T3 resin uptake in the highest dose group. Levels of thyrotropin (TSH) were increased in the highest dose group as a feedback response to the dramatically reduced serum T4 levels.     

Chronic toxicity of 3,4,3',4'-tetrachlorobiphenyl in the marmoset monkey (Callithrix jacchus)

Cotton top marmoset monkeys (Callithrix jacchus) were orally dosed with 3, 1, 0.1 or 0 mg 3,4,3',4'-tetrachlorobiphenyl (TCB)/kg body weight twice per week for 18-23 weeks. Severe toxicity occurred in the highest dose group. Clinical signs of toxicity were a rapid decrease in body weight, alopecia, abnormal nail growth, nodular enlargement of the nipple area and scaly skin. Haematological analysis of peripheral blood revealed mild leukocytosis and anemia. Biochemical alterations observed were elevated triglyceride levels and cholesterol levels. Histopathology revealed dose dependent changes in a variety of tissues. Squamous metaplasia was found in skin and adnexa as well as in salivary glands. In the stomach, parietal cells were decreased and mucus producing cells were increased. The duodenal mucosa was hyperplastic. Ovaries showed an absence of corpora lutea. In the thyroid follicular cell hyperplasia and hypertrophy were noted. Toxicity was less severe in marmoset monkeys dosed with 1 mg TCB/kg, while minor toxic effects were observed in the animals dosed with 0.1 mg TCB/kg. The marmoset monkey appears to be less sensitive to the toxic action of TCB than the rhesus monkey. The pattern of histological and biochemical changes induced by TCB in marmoset monkeys is comparable to that described in humans and in other primate species exposed to PCBs. The marmoset monkey model may be valuable for investigations on human-related toxicity of PCBs.     

Uroporphyrin accumulation in cultured chick embryo hepatocytes: comparison of 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3,4,3',4'-tetrachlorobiphenyl

Uroporphyrin (URO) accumulation caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3,4,3',4'-tetrachlorobiphenyl (TCB) in cultured chick embryo hepatocytes was found to depend on the concentration of the added polyhalogenated aromatic compound, and on either the addition of 5-aminolevulinic acid or the induction of 5-aminolevulinic acid synthase. TCDD alone did not cause more than a slight increase in uroporphyrin, whereas TCB alone caused considerable uroporphyrin accumulation associated with increased 5-aminolevulinic acid synthase activity. However, in the presence of exogenous 5-aminolevulinic acid, TCDD was more potent than TCB in causing uroporphyrin accumulation. The concentrations of TCDD or TCB which maximally induced ethoxyresorufin deethylase activity, an indicator of induced cytochrome P450 activity, were lower than those required for maximal uroporphyrin accumulation. Furthermore, ethoxyresorufin deethylase activity was found to decline at concentrations of TCDD or TCB which caused maximum uroporphyrin accumulation. Pretreatment with 3-methylcholanthrene enhanced uroporphyrin accumulation, whereas addition of inhibitors of cytochrome P450 decreased uroporphyrin accumulation. Uroporphyrin accumulation occurred without a decrease in uroporphyrinogen decarboxylase activity, and was unrelated to the degree of conversion of the polyhalogenated aromatic compounds to water-soluble metabolites. Our results indicate that URO accumulation caused by TCDD and TCB requires two separate actions; (1) induction of cytochrome P450 which occurs at low concentrations of the halogenated chemicals, and (2) increased uroporphyrinogen oxidation which is catalyzed by the induced cytochrome P450 and which occurs at higher concentrations of the halogenated chemicals.     

Neurotransmitter concentrations and binding at dopamine receptors in rats after maternal exposure to 3,4,3',4'-tetrachlorobiphenyl: the role of reduced thyroid hormone concentrations

Polychlorinated biphenyls (PCBs) are environmental contaminants, which accumulate in the food chain and are transferred to the offspring during prenatal development through the placenta and postnatally via breast milk. It is reported that PCBs exert effects on thyroid hormone levels and brain neurotransmitter levels. Both actions may alter neuronal development. The aim of the present study was to investigate, if PCB-induced effects on concentrations of catecholamines and serotonin can be attributed to PCB-induced reductions in thyroid hormone concentrations. In addition, binding to dopamine D(1) and D(2) receptors was examined. Time-mated Wistar rats were treated prenatally with 1 mg 3,4,3',4'-tetrachlorobiphenyl (PCB 77)/kg bodyweight or the vehicle. A third group serving as the positive control received perinatally 5 mg propylthiouracil (PTU)/l drinking water. There were no overt toxic signs in dams or offspring. Thyroid hormone measurements demonstrated effects in dams and offspring up to postnatal day 40. In particular, total T(4) in serum and in the thyroid were decreased in PCB- and PTU-treated dams and offspring. Only PTU exposed rats exhibited significantly increased concentrations of TSH in the serum and pituitary. Measurement of neurotransmitters revealed changes in the PCB-exposed offspring at PND 40, while PTU-treatment was without effect. Dopamine and DOPAC were increased in the medial prefrontal cortex. In adulthood, there were no PCB-related effects on thyroid hormones and neurotransmitters. Binding studies of dopamine D1 and D2 receptors demonstrated that PCB and PTU had no influence on receptor concentration and affinity. Comparison of PCB 77 exposed offspring to PTU exposed offspring demonstrated differential effects on TSH and neurotransmitter levels, the latter result indicating that not all PCB-induced effects on the nervous system can be ascribed to decreases in thyroid hormone concentrations.     

Toxicity of 3,4,5,3',4',5'-hexabrominated biphenyl and 3,4,3',4'-tetrabrominated biphenyl

Immature male rats were given a single equimolar dose (21.3 mumol/kg body wt) of 3,4,5,3',4',5'-hexabromobiphenyl (HBB) or 3,4,3',4'-tetrabromobiphenyl (TBB) and terminated at various times up to 14 days after treatment. Hepatic microsomal aryl hydrocarbon hydroxylase (AHH) activity for the TBB treatment group was maximal at Day 2 and then steadily decreased, whereas this activity was induced in 1 day and remained high for the HBB treatment group. Tissue concentrations of HBB appeared to be unchanged over time whereas tissue concentrations of TBB decreased in a biphasic manner. Rates of in vitro metabolism of TBB with hepatic microsomes from TBB-treated animals showed a similar time-course relationship to AHH induction. HBB caused moderate to severe hepatic changes while TBB-treated rats had only mild hepatic changes. The relative binding of TBB by the hepatic receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was about 10 times that of HBB. The results suggest that even though the receptor-binding affinities imply that TBB should be more toxic than HBB, it is less toxic than HBB because it is metabolized. Studies with the chlorinated analogs of TBB and HBB suggested that PCB behave similarly. These results also suggest that receptor binding and AHH induction do not accurately reflect toxicity for polyhalogenated aromatic hydrocarbons which are metabolized, presumably because continued occupation of the receptor and persistent induction of some enzyme activity are required for toxicity.     

Early and differential decrease in natural retinoid levels in C57BL/Rij and DBA/2 mice by 3,4,3',4'-tetrachlorobiphenyl

3,4,3',4'-Tetrachlorobiphenyl (TCB) administered by weekly ip injections of 1.5 to 100 mg kg-1 for 4 weeks induced a dose dependent decrease in retinoids in female C57BL/Rij and DBA/2 mice (5 to 7 weeks of age). However, the response differed between the two strains of mice. In C57BL/Rij mice, a dose dependent decrease in liver retinol (up to 60%), retinyl palmitate (up to 40%), and serum retinol (up to 80%) occurred, while in DBA/2 mice a decrease in serum retinol (up to 80%) only was observed. The effects of 3,4,3',4'-TCB on retinoid levels were more pronounced than on toxicity (e.g., decrease in thymus and body weight, increase in liver weight, and induction of AHH activity). This finding suggests that reduction in retinoid levels is a very sensitive parameter for the toxicity of polychlorinated biphenyls (PCBs). In addition, in these experiments the induction of aryl hydrocarbon hydroxylase (AHH) did not correlate with the decrease in retinoid levels in C57BL/Rij and DBA/2 mice, suggesting that the mixed function oxidase (MFO) system is not involved.     

Time and dose responses of the reduction in retinoid concentrations in C57BL/Rij and DBA/2 mice induced by 3,4,3',4'-tetrachlorobiphenyl

A single ip dose of 15 mg 3,4,3',4'-tetrachlorobiphenyl (TCB)/kg induced a 30 to 40% reduction of retinol and retinyl palmitate concentrations in hepatic tissue of C57BL/Rij mice within 2 to 4 days. This level of reduction was maintained for about 14 days. The ED50 was 32 mg TCB/kg for hepatic retinol and 17 mg TCB/kg for hepatic retinyl palmitate. In DBA/2 mice, however, no reduction in hepatic retinoids was observed even at doses up to 729 mg TCB/kg. The duration of the reduction in hepatic retinoids did not correlate with the induced aryl hydrocarbon hydroxylase (AHH) activity in C57BL/Rij mice. These data suggest that AHH and related enzymes are not directly involved in the TCB-induced reduction in retinoids in these mouse strains. No significant differences in the accumulation of TCB in hepatic tissues of C57BL/Rij and DBA/2 mice were observed; however, the estimated elimination rate in C57BL/Rij was two times faster than that in DBA/2 mice. In serum of DBA/2 mice, a rapid 50% decline in the concentration of retinol was observed after only 2 to 6 hr, remaining at the reduced value for about 14 days. The ED50 for serum retinol was 1 to 2 mg TCB/kg. Only a transient reduction in serum retinol, disappearing within 48 hr, was observed in the C57BL/Rij mouse. TCB accumulated to an almost 15-fold higher extent in serum of DBA/2 mice as compared with C57BL/Rij mice. The effect of TCB on retinoids in a few other strains of mice and in the Sprague-Dawley rat showed a reduction in serum retinol rather than in hepatic retinoids.     

Assessment of the chloracnegenic response induced by 3,4,3',4'-tetrachloroazoxybenzene in mice

Chloracne is a follicular hyperkeratosis produced by exposure to certain halogenated aromatic compounds. The rabbit ear bioassay has been used successfully for testing the acnegenic activity of compounds, but the lack of reference data in this species limits its usefulness in correlating chloracne to other toxic effects such as skin carcinogenesis. In this study, a prototype chloracnegen, 3,4,3',4'-tetrachloroazoxybenzene (TCAOB), was used. Five strains of mice (hairless, rhino, rhino+, DBA/2J, and C57BL/6) were treated topically with 100 microliters of 0.001, 0.01, or 0.1% TCAOB daily for 3-9 wk. Skin and liver histology were performed and hepatic enzyme activities measured. At the 0.001% TCAOB level, induction of hepatic aniline hydroxylase and cytochrome P-450 occurred in the C57BL/6 mice and induction of cytochrome c reductase occurred in the rhino mice. Dose-dependent gross and histologic skin lesions, characteristic of follicular hyperkeratosis, were observed in the rhino and hairless strains at the 0.01% and 0.1% levels. These two strains also had induction of hepatic cytochrome c reductase, cytochrome P-450, and aniline hydroxylase at TCAOB concentrations of 0.01 or 0.1%. These results suggest that the rhino and hairless strains of mice may be useful in the study of chloracne.     

The pharmacokinetics of 2,2',5,5'-tetrachlorobiphenyl and 3,3',4,4'-tetrachlorobiphenyl and its relationship to toxicity

The pharmacokinetics of two toxicologically diverse tetrachlorobiphenyls (TCBs) were measured in mice. After dosing to apparent steady-state conditions, 2,2',5,5'-TCB was found to have a tissue elimination half-life of between 1.64 and 2.90 days. The half-life of 3,3',4,4'-TCB was similar, ranging from 1.07 to 2.60 days. Systemic clearance and volume of distribution estimates were also similar for the two TCB isomers. The 3,3',4,4'-isomer had a substantially greater partitioning from serum into adipose, liver, and thymic tissues. With dosing regimens developed using these measured pharmacokinetic parameters, experiments were undertaken to compare toxic potency of these two TCBs when similar tissue concentrations of the two isomers were achieved in target and storage tissues. These studies demonstrated that thymic atrophy occurs at lower 3,3',4,4'-TCB doses and tissue concentrations than those required to produce hepatotoxicity. These two organ toxicities were produced only by 3,3',4,4'-TCB despite the fact that equivalent or higher tissue concentrations of 2,2',5,5'-TCB were achieved in vivo in all tissues. We conclude that the in vivo difference in the toxic potency of these two TCB isomers does not result from the significant differences in their tissue disposition, elimination, and ultimate bioaccumulation.     

Metabolism of 2,2',5,5'-tetrachlorobiphenyl: formation of mono- and bis-methyl sulphone metabolites with a selective affinity for the lung and kidney tissues in mice

1. Distribution in mice of 2,2',5,5'-tetrachloro[14C]biphenyl has been studied by autoradiography. Radioactivity was specifically localized in the bronchial epithelium, the lung parenchyma, the kidney cortex and the adipose tissue. 2. Bis(methylsulphonyl)-2,2',5,5'-tetrachlorobiphenyl, a hitherto unknown metabolite of 2,2',5,5'-tetrachlorobiphenyl, has been identified in lung, kidney and liver of mice. 3- and 4-Methylsulphonyl-2,2'5,5'-tetrachlorobiphenyl were also present. 3. The ratio of the contents of 3- and 4-methylsulphonyl-2,2',5,5'-tetrachlorobiphenyl in the liver was 1.12 after 12 days. A lower ratio in lung and kidney indicates a high affinity of these tissues for the 4-methyl isomer.     

Binding of a metabolite of 3,4,3',4'-tetrachlorobiphenyl to transthyretin reduces serum vitamin A transport by inhibiting the formation of the protein complex carrying both retinol and thyroxin

The mechanism of serum vitamin A reduction by polychlorinated biphenyls was studied at the level of the plasma transport protein system for vitamin A. Analysis of [3H]retinol-labeled serum proteins by polyacrylamide gel electrophoresis (PAGE) showed association of retinol with two proteins that were identified as retinol binding protein (RBP) and the RBP complex with transthyretin (TTR). The amount of [3H]retinol radioactivity in the serum as well as the label associated with the binding proteins was strongly reduced by 3,4,3',4'-tetrachlorobiphenyl (TCB). A possible interaction of TCB with the retinol binding proteins was investigated, using radiolabeled TCB. Analysis of the plasma proteins by PAGE revealed the presence of four peaks of 3H-TCB label, the major ones being associated with lipoproteins and TTR. No 3H-TCB radioactivity was found in the region of the gel where RBP or the RBP-TTR complex was located. HPLC analysis of the radioactive compound associated with TTR showed the presence of a metabolite of TCB, rather than the parent compound. These data indicate a direct interaction of a metabolite of TCB with TTR leading to an inhibition of formation of the serum transport protein complex carrying both retinol and thyroxin. A model is proposed, which may explain certain characteristic toxicopathological lesions observed in species exposed to polychlorinated biphenyls and related compounds (TCDD, PBBs, etc.).     

Effect of micelle fatty acid composition and 3,4,3', 4'-tetrachlorobiphenyl (TCB) exposure on intestinal [(14)C]-TCB bioavailability and biotransformation in channel catfish in situ preparations.

Polychlorinated biphenyls are transferred in the diet along aquatic food chains. This study investigated the effect of dietary micelle composition and 3,4,3',4'-tetrachlorobiphenyl (TCB) exposure upon the subsequent systemic bioavailability and intestinal metabolism of [(14)C]-TCB in a catfish in situ intestinal preparation. Initial in vitro experiments examined the solubility of [(14)C]-TCB in micelles of varying fatty acid composition. Micelles composed of single fatty acids demonstrated greater [(14)C]-TCB solubility with those fatty acids of longer chain length. Similarly, micelles of the long-chain fatty acid, linoleic acid, solubilized more [(14)C]-TCB than mixed micelles formulated from equal amounts of myristic (14:0), palmitic (16:0), stearic (18:0), or linoleic (18:2) acids. Systemic bioavailability of [(14)C]-TCB (60 microM) from an in situ perfused intestinal preparation was 2.2-fold greater when delivered to the intestine in linoleic acid micelles as compared to the mixed micelle preparation. Catfish exposed in vivo to either 0.5 or 5.0 mg TCB/kg feed for 10 days resulted in a 45 to 47% decrease in the subsequent systemic bioavailability of [(14)C]-TCB in the in situ intestinal preparation. Total intestinal cytochrome P450 content was not significantly affected by TCB preexposure. Immunodetectable CYP1A was found only in the 5.0 mg TCB/kg diet treatment. Corresponding intestinal aryl hydrocarbon hydroxylase (AHH) activities were 2.46 +/- 1.16, 2.43 +/- 1.58, and 11.35 +/- 10.25 pmol/min/mg protein for the control, 0.5, and 5 mg TCB/kg diet groups, respectively. [(14)C]-TCB in the in situ preparation was metabolized to only a small degree upon a single pass through the intestinal mucosa of the catfish. High variability and low rates of metabolism precluded the association of the magnitude of metabolism with dietary TCB pretreatment. Analysis of tissue sample extracts demonstrated 4 minor peaks, 3 of which were tentatively identified by co-elution with standards as 2-OH-3,4,3',4'-TCB, 4-OH-3,5,3',4'-TCB, and 5-OH-3, 4,3',4'-TCB. A fourth remains unidentified. Histological changes in the intestine such as thinning of the submucosa and increased numbers of goblet cells were evident at the 5.0 mg TCB/kg diet dose. These results suggest that TCB intestinal bioavailability may be linked to micelle composition as well as TCB exposure history. Furthermore, single pass intestinal metabolism appears to be a minor contributor to the biotransformational modification of dietary TCB.     

Elimination and distribution of 2,2',4,5'-tetrachlorobiphenyl in laying hens

Laying hens were given a single oral dose of 2,2',4,5'-tetrachloro[14C]biphenyl ([14C]TCB). Within 11 days of administration, 54.8% of the original dose was excreted in the faeces. Examination of eggs laid within this period showed that 11.7% of the original dose was present in the yolks. The biological half-life of [14C]TCB in hens was 7 days. In hens killed on day 7, radioactivity could be detected in all the main tissues and organs. In both faeces and yolk, about 60% of the radioactivity could be attributed to metabolites.     

Effect of 3,3',4,4'-tetrachlorobiphenyl and 2,2',4,4',5,5'-hexachlorobiphenyl on the induction of hepatic lipid peroxidation and cytochrome P-450 associated enzyme activities in rats

Polychlorinated biphenyls (PCBs) are environmental contaminants that have been widely used for various industrial purposes. In spite of numerous studies on PCBs, however, their mechanism of toxicity remains unknown. The role of cytochrome P-450 in PCBs induced hepatic lipid peroxidation is controversial. Therefore, the present study was undertaken to study the mechanism of action of two PCBs and their role in cytochrome P-450 induction and lipid peroxidation, determined in vivo and during the incubation of subcellular fractions. We also examined whether agonist/antagonist activities between the two PCBs were occurring. Two PCBs were studied: 3,3',4,4'-tetrachlorobiphenyl (PCB-77), a non-ortho-substituted, coplanar PCB; and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153), a di-ortho-substituted, non-planar PCB. Groups of male Sprague-Dawley rats were given a single i.p. injection of one of the two PCBs (at doses of 30, 150, or 300 micromol/kg), both PCBs (at doses of 30 or 150 micromol/kg), or vehicle alone. Rats were sacrificed after 2, 6, or 24 h; or 2, 6, or 10 days. Cytochrome P-450 induction occurred as early as 2 h with PCB-77 and 24 h with PCB-153. Significant increases in thiobarbituric acid reactive substances (TBARS) content in liver tissue occurred 2, 6 and 10 days after treatment with PCB-77 and PCB-153; it was unclear whether these PCBs were synergistic in their induction of TBARS formation. Liver microsomal fractions incubated with NADPH only showed increased TBARS formation at the highest doses of PCB-77 and PCB-153 after 6 days. The results indicate that both PCBs induced cytochrome P-450 enzymes and enhanced lipid peroxidation in liver and subcellular fractions but with different potencies and onsets of action. The results also indicate a larger time difference between cytochrome P-450 induction and lipid peroxidation for PCB-77. Thus, both PCB-77 and PCB-153 are toxic to cells, but may act via different mechanisms to induce their effects.     

Formation of quinonoid-derived protein adducts in the liver and brain of Sprague-Dawley rats treated with 2,2',5, 5'-tetrachlorobiphenyl

A possible role for metabolic activation of 2,2',5, 5'-tetrachlorobiphenyl (TCB) to quinonoid metabolites was investigated in vitro in rat liver microsomes and in vivo in male Sprague-Dawley rats. Incubation of TCB with phenobarbital-induced rat liver microsomes resulted in metabolism of TCB to 3-hydroxy-TCB (3-OH-TCB) and 3,4-dihydroxy-TCB (3,4-diOH-TCB), which were further oxidized to form a reactive intermediate that bound to liver proteins. The predominant species observed in the Raney nickel assay for cysteinyl adducts was identified as 3,4-diOH-TCB, consistent with an adduct having the structure 5-cysteinyl-3,6-dichloro-4-(2', 5'-dichlorophenyl)-1,2-benzoquinone. This adduct may arise via the Michael addition of the sulfhydryl group of cysteine to 3, 6-dichloro-4-(2',5'-dichlorophenyl)-1,2-benzoquinone (Cl(4)PhBQ). Metabolism of 3-OH-TCB by phenobarbital-induced microsomes in the presence of either NADPH or cumene hydroperoxide as a cofactor resulted in the formation of adducts. Dose-dependent formation of cysteinyl adducts was observed in liver cytosolic protein from rats treated with a single dose of TCB (0-200 mg/kg) by gavage. By regression analysis, the TCB adducts decayed with a half-life of 2. 03 +/- 0.131 days (mean +/- SE), which is approximately 2.5-fold shorter than the endogenous half-life for liver cytosolic protein in rat liver, suggesting adduct instability. Saturable formation of TCB adducts was observed in liver cytosolic protein of rats receiving multiple doses of TCB over 5 days. The levels of Cl(4)PhBQ-derived adducts were 2.1-fold greater than the estimated steady-state levels predicted by the single-dose treatment [97.7 +/- 13.2 vs 45.7 +/- 3. 73 (pmol/g)/(mg/kg of body weight)], suggesting induction of metabolism. A single cysteinyl adduct, inferred to be 5-cysteinyl-3, 6-dichloro-4-(2',5'-dichlorophenyl)-1,2-benzoquinone, was detected in brain cytosolic protein of rats treated with multiple doses of TCB with levels of 15.2 (pmol/g)/(mg/kg of body weight). Implied involvement of a reactive quinone in the liver and brain of TCB-treated rats supports the idea that quinonoid metabolites may be important contributors to PCB-derived oxidative damage to genomic DNA.     

人参皂苷体内代谢及其产物的生物活性

人参皂苷(ginsenoside)是从人参中提取出来的萜类化合物,是人参诸多药理药效作用的主要活性成分。天然人参皂苷口服难以被直接吸收,必须经过体内代谢后,其产物才能发挥生物活性。然而,迄今国内尚未检索到人参皂苷体内代谢过程比较系统的研究报道。因此,本文从以下4个方面概述下人参皂苷在体内的代谢研究:一是人参皂苷胃酸液、肠道菌、其他微生物的去糖基化;二是代谢产物通过被动扩散的方式进行吸收;三是代谢产物在肝脏中的酯化和聚集;四是代谢产物的生物活性。     

Decreased pulmonary drug metabolism in mice treated with the PCB metabolite 4-methylsulphonyl-2,2',5,5'-tetrachlorobiphenyl

4-Methylsulphonyl-2,2',5,5'-tetrachlorobiphenyl (4-MeSO2-TCB) is a major polychlorinated biphenyl (PCB) metabolite present in lung tissue of PCB-exposed human subjects. After treatment of mice with 4-MeSO2-TCB (100 mg/kg), the pulmonary N-demethylation of aminopyrine in vitro was significantly decreased, while hepatic N-demethylation was concomitantly increased, as compared to tissue from control mice. Treatment of mice with 4-MeSO2-TCB also decreased the in vivo pulmonary covalent binding of o,p'-DDD, while the in vivo hepatic covalent binding was increased. The results indicate that 4-MeSO2-TCB inhibits or represses a cytochrome P-450-dependent enzyme activity in the mouse lung, while in contrast this activity is induced in the mouse liver.     

Effects of 3,3',4,4'-tetrachlorobiphenyl in the brain of the neonatal mouse

To study the retention of TCB in the brain of the immature mouse and its effects on the muscarinic cholinergic receptors in the cerebral cortex and hippocampus, [14C]TCB and TCB were administered to 10-day-old mice as a single peroral dose of 1.5 MBq/kg body wt and 0.41 mg or 41 mg/kg body wt, respectively. The mice were killed 24 h or 7 days after treatment. The amount of radioactivity in the whole brain decreased by 78% between 24 h and 7 days after administration. The density of muscarinic receptors was measured using the muscarinic antagonist [3H]QNB. A significant decrease (16%) in specific [3H]QNB binding was observed in the hippocampus 7 days after treatment. Despite the relatively rapid elimination of TCB from the immature mouse brain, a single low dose of TCB given during the period of rapid development of the cholinergic system appeared to affect the muscarinic cholinergic receptors in the immature mice.     

Transport of 2,4,5,2',4',5'-hexachlorobiphenyl by lipoproteins in vivo

Lipoproteins are currently being recognized as transport vehicles for lipophilic drugs and xenobiotic chemicals in plasma. The weight of in vitro evidence suggests lipoproteins as the principal carries of 2,4,5, 2',4',5'-hexachlorobiphenyl (6-CB) in plasma from normolipidemic rats and humans. The present study examined the in vivo distribution of 6-CB among lipoproteins as well as the influence of time on the absolute amount and proportion of 6-CB associated with each density fraction. Plasma obtained between 1 min and 24 hr after an iv injection of 6-[14C]CB was separated into very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) fractions by sequential ultracentrifugation. The in vivo results corroborate the in vitro data which suggest LDL to be a major transport vehicle for 6-CB in plasma. However, the preference of 6-CB for LDL existed for only a short time following injection. From 6 to 24 hr after administration of 6-CB, there was a shift in the distribution of the PCB from LDL to HDL and the remaining protein-rich bottom fraction. By 24 hr, the proportion of 6-CB in LDL had declined from 80% of the plasma concentration to 30%, while that in HDL had doubled. Furthermore, the amount of 6-CB in the bottom fraction accounted for 35% of the radioactivity in plasma at 24 hr as opposed to less than 5% up to 1 hr after administration. The absolute contents of 6-CB in both HDL and the bottom fraction also increased during the later time points. Analysis of the decay curves of 6-CB among the various lipoproteins further substantiated a change in the distribution of 6-CB over time. The decay of 6-CB in LDL most closely resembled its disappearance from plasma. The content of 6-CB remaining in plasma at 24 hr was equally distributed among LDL, HDL, and the bottom fraction. Changes in lipoprotein composition during the 24-hr period could not explain 6-CB redistribution, since there were no significant differences in the proportion of constituents comprising VLDL, LDL, HDL, or the bottom fraction.