Separation of pure polychlorinated biphenyl isomers into two types of inducers on the basis of induction of cytochrome P-450 or P-448

Goldstein, Joyce A.; Hickman, Patricia; Bergman, Hinda; McKinney, James D.; Walker, Michael P.

doi:10.1016/0009-2797(77)90073-4

Cited by 250 publications

(54 citation statements)

References 30 publications

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“…4-CB induces cytochrome P-448-dependent enzymes and 6-CB induces P-450-dependent pathways in livers of offspring exposed to these congeners transplacentally and during lactation. Thus, the perinatal and adult livers respond to PCBs in much the same way (64)(65)(66). Our studies demonstrate that in developing rats, like adults, individual congeners are P-450 or P-448 inducers and that neonates may be more sensitive to PCBmediated increases in enzyme activities than adults.…”

Section: Modifications Of Ontogenymentioning

confidence: 99%

Metabolic activation/deactivation reactions during perinatal development.

Lucier¹,

Lui²,

Lamartiniere³

1979

Environ Health Perspect

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The role of metabolic activation/deactivation reactions during development is evaluated in relation to developmental pharmacology and toxicology. Enzyme systems evaluated include the mixed-function oxidases (aryl hydrocarbon hydroxylase and oxidative demethylation), epoxide hydration and conjugation (glutathione conjugation, sulfation, and glucuronidation). Placental transfer and milk secretion of chemicals are discussed in relation to maternal, placental, and fetal metabolism. Normal patterns of enzyme development can be modified in two ways: (1) enzyme induction and (2) enzyme imprinting. Postnatal induction of the mixed-function oxidases and glucuronyl-transferase following treatment of pregnant rats with TCDD is shown to be caused primarily by newborn exposure to TCDD in milk. Structure-activity relationship are defmed for the perinatal induction of hepatic enzymes by the pure PCBs. PCBs are divided into two classes: P-450 inducers and P-448 inducers. Imprinting or programming of hepatic metabolism is a function of the sexual differentiation of enzyme activity; male and female activities are similar in prepubertal animals, whereas pronounced sex differences are evident in adults. Treatment of newborn rats (days 2-6) with diethylstilbestrol or testosterone resulted in a feminization (decrease) of mixed-function oxidation and glucuronidation in adult males. No changes were seen in immature males or females or adult females. This effect appears to be irreversible and is under pituitary-hypothalamicgonadal control. In addition to the feminization of enzyme activity, neonatal exposure to hormonally active chemicals also feminizes the hepatic response to cadmium in resultant adult animals.

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Section: Modifications Of Ontogenymentioning

confidence: 99%

Metabolic activation/deactivation reactions during perinatal development.

Lucier¹,

Lui²,

Lamartiniere³

1979

Environ Health Perspect

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“…The moderately chlorinated isomer groups also contain most of the mixedfunction oxidase (MFO)-inducing congeners. Two of the three pure 3-MC-type inducers and all but two of the mixed-type inducers are penta-, hexa-, or heptachlorobiphenyls (17)(18)(19)(20)(21)(22)(23)(24). The more highly chlorinated congeners are generally less available to organisms both because they are more tightly bound with soils and sediments and because they usually are present in lower quantities in the environment.…”

mentioning

confidence: 99%

“…The more highly chlorinated congeners are generally less available to organisms both because they are more tightly bound with soils and sediments and because they usually are present in lower quantities in the environment. Congeners with less chlorination are more readily metabolized and eliminated and so do not tend to bioaccumulate as highly (17,18,25).…”

mentioning

confidence: 99%

Environmental occurrence, abundance, and potential toxicity of polychlorinated biphenyl congeners: considerations for a congener-specific analysis.

McFarland

Clarke

1989

Environ Health Perspect

616

279

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Polychlorinated biphenyls (PCBs) as environmental contaminants often cannot be adequately described by reference to Aroclors or to total PCBs. Although there are 209 possible PCB configurations (congeners), perhaps half that number account for nearly all of the environmental contamination attributable to PCBs. Still fewer congeners are both prevalent and either demonstrably or potentially toxic. If potential toxicity, environmental prevalence, and relative abundance in animal tissues are used as criteria, the number of environmentally threatening PCB congeners reduces to about thirty-six. Twenty-five of these account for 50 to 75% of total PCBs in tissue samples of fish, invertebrates, birds, and mammals.A few PCB congeners that are sterically similar to 2,3,7,3,7, are directly toxic. Other PCB congeners, as well as those that are directly toxic, may also be involved in toxicity indirectly by stimulating the production of (inducing) bioactivating enzyme systems. The most consequential of these have the ability to induce aryl hydrocarbon metabolizing mixed-function oxidases (MFOs). A result can be an increased capacity for bioactivation of otherwise nontoxic foreign compounds such as certain polynuclear aromatic hydrocarbons (PAH) to cytotoxic or genotoxic metabolites. The effectiveness of specific PCB congeners as inducers of different types of cytochrome P-450-dependent MFO systems is determined by their stereochemistry. Although MFO induction is not a proximate cause, it is a strong correlate of certain kinds of toxicities. Structural patterns can thus be used to discriminate among PCB congeners on the basis of toxic potential, if not entirely on toxicity per se. Congeners that demonstrate 3-methylcholanthrene-type (3-MCtype) and mixed-type MFO induction have the greatest toxic potential. These congeners most closely resemble 2,3,7,8-TCDD in their structures and in their toxic effects. The larger group of phenobarbital-type (PBtype) inducers have considerably less potential for contributing to toxic effects. Weak inducers and noninducing congeners have the least potential for toxicity.Using the rationale described in this paper, we assigned the most environmentally threatening PCB congeners to four groups. Congeners assigned to Group 1 are considered most likely to contribute to adverse biological effects attributable to PCBs in an environmental sample. Group 1A contains the three most potent (pure 3-MC-type inducer) congeners, IUPAC numbers 77, 126, and 169. Six congeners, numbers 105, 118, 128, 138, 156, and 170, are assigned to Group 1B. These congeners are mixed-type inducers that have been reported frequently in environmental samples. Group 2 congeners are PB-type inducers that are also prevalent in the environment; these include numbers 87, 99, 101, 153, 180, 183, and 194. Group 3 congeners, numbers 18,44,49,52,70,74, 151, 177, 187, and 201, are weak or noninducers, but they occur frequently in the environment or in high concentrations in animal tissues relative to other PCB congeners, and so may be of ...

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“…The terms PB-type and 3-MC-type will be used here to indicate these two classes of inducers. A number of drugs and pesticides, such as DDT and chlordane, and certain halogenated biphenyl isomers behave as PB type inducers (Conney, 1967;Goldstein et al, 1977). Among the 3-MC-class of J inducers are other polycyclic aromatic hydrocarbons, chlorinated dibenzodioxin and dibenzofurans, and certain halogenated biphenyls (Cooney, 1967;Poland and Glover, 1973;Goldstein et al, 1977).…”

Section: Induction Of Microsomal Monooxygenasesmentioning

confidence: 99%

“…Aroclor 1254 was specifically selected because it is about equipotent as both a PB and 3-MC type inducer (Goldstein ~ ~., 1977). A point worth emphasizing is that the cytochrome P-450 system is ac tive in metabolizing a great variety of xenobiotics, and is induced by Page 67.…”

Section: The Research Problem and Experimental Approachmentioning

confidence: 99%

Xenobiotic monooxygenase activity and the response to inducers of cytochrome P-450 during embryonic and larval development in fish

Binder¹

1981

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Separation of pure polychlorinated biphenyl isomers into two types of inducers on the basis of induction of cytochrome P-450 or P-448

Cited by 250 publications

References 30 publications

Metabolic activation/deactivation reactions during perinatal development.

Metabolic activation/deactivation reactions during perinatal development.

Environmental occurrence, abundance, and potential toxicity of polychlorinated biphenyl congeners: considerations for a congener-specific analysis.

Xenobiotic monooxygenase activity and the response to inducers of cytochrome P-450 during embryonic and larval development in fish

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