4,4′-Dichlorobiphenyl: Distribution, metabolism, and excretion in the dog and the monkey☆,☆☆
Abstract
The tissue distribution, metabolism, and excretion of 4,4′-dichlorobiphenyl (4,4′-DCB) were investigated in beagle dogs and cynomolgus monkeys (Macaca fascicularis). Following a single iv dose of [14C]4,4′-DCB (0.6 mg/kg) excreta, blood, and tissues were collected at time intervals ranging from 15 min to 28 days for determination of levels of parent compound and its metabolites. Elimination of the parent PCB in the blood of both species was biphasic with a terminal-phase elimination rate constant of 0.018 hr−1 for the dog and 0.002 hr−1 for the monkey. By 24 hr the dog excreted 50% of the dose in the feces (43%) and the urine (7%). The percentage dose remaining was found largely as parent compound in the fat with some in muscle and skin. By 5 days 90% of the dose was excreted. In contrast, during the first 24 hr the monkey excreted less than 15% of the dose with less than 1% in the feces. The percentage dose remaining in the body was localized as parent compound in fat (33%) with lesser amounts in skin and muscle. By 28 days 59% of the dose was excreted, primarily in the urine. In anesthetized dogs 33% of the dose was excreted into the bile within 2 hr, while the monkey excreted only 0.4% of the dose by that route. The data present a clear species variation between the dog and the monkey in both the rate and route of excretion of 4,4′-DCB.
References (15)
- M.Th.M. Tulp et al.
The Metabolism of 4,4′-dichlorobiphenyl in Rats and Frogs
Chemosphere
(1976) - M.M. Abou-El-Makarem et al.
Biliary excretion of foreign compounds: Species differences in biliary excretion
Biochem. J.
(1967) - H.G. Boxenbaum et al.
Statistical estimations in pharmacokinetics
J. Pharmacokinet. Biopharm.
(1974) - M. Gibaldi et al.
- R. Hinz et al.
Comparative metabolism of PCB isomers by three species of fish and the rat
Bull. Environ. Contamin. Toxicol.
(1977) - O. Hutzinger et al.
Cited by (17)
Metabolism and body-burden of PCBs in lactating dairy cows
1999, ChemosphereThis paper uses data from a detailed 4 month PCB mass balance study on lactating cows fed a naturally contaminated background diet to quantify the metabolism and body-burdens of a range of PCB congeners. Dietary intake fluxes and milk and faecal output fluxes reported previously are combined with subcutaneous fat and blood PCB concentrations and with data from tissue/organ samples from a slaughtered animal to estimate the degree of metabolism within the cow. A total body burden is derived, showing that fat deposits account for ∼98 % of total PCB present in the lactating cow. The daily intake through feed (ng day−1) accounted for between 0.9 and 1.5 % of the total body burden for persistent congeners (e.g. PCB 153) and up to 43 % for those congeners which are readily metabolised (e.g. PCB 52). Detailed balances for a range of tri- to octa-chlorinated PCBs are presented and clearly demonstrate that many congeners are metabolised effectively by lactating dairy cows (e.g. PCB 149) whilst others are efficiently transferred to human dairy food products. An approach to predicting the degree of metabolism for individual PCB congeners is presented which gives good agreement with observations.
CB pattern in the harbour porpoise: Bioaccumlation, metabolism and evidence for cytochrome p450 IIB activity
1995, ChemosphereMetabolism of chlorobiphenyls (CBs) was studied in harbour porpoise by comparing patterns of CB-X/CB-153 ratios in blood, brain, liver and blubber with the patters in herring, the main food source. The CBs were classified in five groups, based on the presence/absence of vicinal H-atoms (vic. Hs) in meta,para (m,p) and/or ortho, meta (o,m) positions and the number of ortho-Cl-atoms (ortho-Cls).
Plots of CB-X/CB-153 ratios in porpoise tissue vs the ratios in herring appeared to be linear for each CB group in all tissues. Slopes of these plots (metabolic slopes) were used as quantitative indicators of metabolic activity. In this way, activity of PB-type isozymes of the P450 monooxygenase system was apparent: in contrast to existing literature data, harbour porpoise appears to be able to metabolize congeners with m,p vic. Hs, even in the presence of more than 2 ortho-Cls. The presence of 3-MC-type (MC-type) isozymes was also detected.
The metabolic slopes were also used as basis for risk assessment. Due to their metabolism the most toxic non-ortho CBs were not present in the tissues at detectable levels. We suggest a risk assessment approach which takes this into account. It is considered to be an alternative and more reliable basis for risk assessment than the use of toxic equivalent factors.
The results support the model of equilibrium distribution of CBs in harbour porpoise and the role of blood as central transport medium. The model has been developed for persistent compounds; it appears to hold for metabolizable CB congeners as well.
Dermal absorption of phthalate diesters in rats
1989, Fundamental and Applied ToxicologyThis study examined the extent of dermal absorption of a series of phthalate diesters in the rat. Those tested were dimethyl, diethyl, dibutyl, diisobutyl, dihexyl, di(2-ethylhexyl), diisodecyl, and benzyl butyl phthalate. Hair from a skin area (1.3 cm in diameter) on the back of male F344 rats was clipped, the [14C]phthalate diester was applied in a dose of 157 μmol/kg, and the area of application was covered with a perforated cap. The rat was restrained and housed for 7 days in a metabolic cage that allowed separate collection of urine and feces. Urine and feces were collected every 24 hr, and the amount of 14C excreted was taken as an index of the percutaneous absorption. At 24 hr, diethyl phthalate showed the greatest excretion (26%). As the length of the alkyl side chain increased, the amount of 14C excreted in the first 24 hr decreased significantly. The cumulative percentage dose excreted in 7 days was greatest for diethyl, dibutyl, and diisobutyl phthalate, about 50–60% of the applied 14C; and intermediate (20–40%) for dimethyl, benzyl butyl, and dihexyl phthalate. Urine was the major route of excretion of all phthalate diesters except for diisodecyl phthalate. This compound was poorly absorbed and showed almost no urinary excretion. After 7 days, the percentage dose for each phthalate that remained in the body was minimal and showed no specific tissue distribution. Most of the unexcreted dose remained in the area of application. These data show that the structure of the phthalate diester determines the degree of dermal absorption. Absorption maximized with diethyl phthalate and then decreased significantly as the alkyl side chain length increased.
The metabolism of xenobiotics and endogenous compounds by the constitutive dog liver cytochrome P450 PBD-2
1988, Archives of Biochemistry and BiophysicsWe have investigated the metabolism of polychlorinated biphenyls and endogenous steroids by the major phenobarbital (PB)-inducible hepatic cytochromes P450 in dogs and rats, PBD-2 and PB-B, respectively. Previous results from our laboratory indicate that dog PBD-2 purified from microsomes of PB-treated animals is similar to rat PB-B with respect to structure and the regioselective metabolism of warfarin and androstenedione. The results also strongly suggest that PBD-2 is the P450 form responsible for metabolizing 2,2′,4,4′,5,5′-hexachlorobiphenyl (245-HCB) in liver microsomes from untreated dogs. In the present study, a cytochrome P450 with similar Chromatographic behavior to that of PBD-2 has been purified from liver microsomes of untreated dogs. This protein is identical to PBD-2 based on (i) mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, (ii) reactivity with anti-PBD-2 IgG, (iii) amino-terminal sequence, and (iv) 245-HCB metabolite profile. Induction and antibody-inhibition data suggest that PBD-2 is responsible for the metabolism of 2,2′,3,3′,6,6′-hexachlorobiphenyl (236-HCB) in microsomes obtained from both untreated and PB-treated dogs. In contrast, metabolism of 4,4′-dichlorobiphenyl (4-DCB) by dog microsomes is poor, and does not appear to be catalyzed to a significant extent by PBD-2. Antibody-inhibition studies with intact microsomes corroborate previous results that androstenedione is metabolized by purified PBD-2 to the same major metabolite (16β-OH androstenedione) produced by rat PB-B. Dog PBD-2 metabolizes progesterone primarily to the 21-OH metabolite, while metabolism by rat PB-B leads to the formation of the 16α-OH product. On the other hand, upon Ouchterlony double-immunodiffusion analysis, anti-PBD-2 IgG reacts strongly with PB-B but not PB-C, the major rat liver progesterone 21-hydroxylase. The data suggest that dog PBD-2 is a constitutive P450 important in the metabolism of various PCBs and endogenous steroids. Dog PBD-2 and rat PB-B appear to be similar enzymes, yet they differ in their regioselective metabolism of progesterone.
The kinetics of individual polychlorinated biphenyl congeners in female harbour seals (Phoca vitulina), with evidence for structure-related metabolism
1987, Aquatic ToxicologyFemale harbour seals were held in captivity. During a period of two years, one group received contaminated fish from the Dutch Wadden Sea, while a second group was given relatively clean fish from the Atlantic Ocean. Concentrations of individual polychlorinated biphenyl (PCB) congeners were measured in fish, seal blood and occasionally in faeces of seals.
The PCB patterns within each of these three ‘matrices’ were highly similar, but differed between them. According to their degree of biomagnification in seal blood, PCBs could be divided into persistent congeners and congeners with lowered concentrations. This behaviour was related to molecular structural features; congeners showing lowered concentrations possessed vicinal H atoms at either a meta-para position or at an ortho-meta position. Only in the latter case the number of ortho-chlorines present influenced the toxicokinetical behaviour of the congeners; lowered concentrations were only observed for mono-ortho chlorine containing congeners.
Enzyme-mediated metabolism is the most probable cause for the relatively low contribution of such congeners to the PCB pattern in seal blood.
On a wet-weight basis, the concentrations of all congeners were lower in seal blood than in their food, but when expressed on a lipid basis, the non-metabolized congeners were biomagnified. At the end of the experiment, the PCB concentrations were significantly lower (P < 0.001) in the seals which had received fish from the Atlantic Ocean.
Metabolism-related spectral characterization and subcellular distribution of polychlorinated biphenyl congeners in isolated rat hepatocytes
1986, Biochemical PharmacologyThe disposition and biotransformation of 4,4'-dichlorobiphenyl (4-DCB), 2,2',3,3',6,6'-hexachlorobiphenyl (236-HCB), and 2,2',4,4',5,5'-hexachlorobiphenyl (245-HCB) were studied in isolated rat hepatocyte suspensions. The polychlorinated biphenyls (PCBs) were taken up rapidly by the cells but incompletely metabolized. Metabolism followed first-order Michaelis-Menten kinetics for 20 min and plateaued by 60 min, at which point only 32% of 4-DCB (0.005 to 100 μM) and 60% of 236-HCB (0.001 to 100 μM) were metabolized, while metabolism of 245-HCB was not detected (0.1 to 200 μM). Kinetic studies revealed that both 4-DCB and 236-HCB were metabolized by two Michaelis-Menten processes, displaying high- and low-affinity binding. Readdition of congener once metabolism plateaued resulted in a reinitiation of metabolism with the same proportion of metabolites produced. The termination of metabolism was not due to destruction of the mixed-function oxidases or to depletion of cofactors. The metabolism of PCB congeners is influenced by the affinity of the congener for cytochrome P-450 and partitioning of the congener within the hepatocyte. Analysis of absorbance differences (Δ absorbance 390-240 nm) of equimolar concentrations of congener (100 μM) revealed that 236-HCB displayed the greatest affinity of binding to cytochrome P-450 followed by 4-DCB, while 245-HCB showed virtually no binding. Microsomal preparations demonstrated equivalent but greater absorbance values. Subcellular distribution of 14C-labeled congener and its metabolites showed that the majority of radioactivity appeared in the cytosolic fraction, representing 70% of the dose added for each congener. Cytosolic binding of congener and metabolites may influence both the availability of congener to cytochrome P-450 and the excretion rate of metabolites from the cell.
- ☆
Presented in part at the Eighteenth Annual Meeting of the Society of Toxicology, March 11–15, 1979 New Orleans, La.
- ☆☆
Supported by NIEHS Contract N01-ES-72111.