Biotransformation and porphyrinogenic action of hexachlorobenzene and its metabolites in a primary liver cell culture

Debets, F.M.H.; Reinders, Jan-Hendrik; Debets, Alexander J.; Lössbroek, T.G.; Strik, J.J.T.W.A.; Koss, G.

doi:10.1016/0300-483x(81)90128-1

Cited by 36 publications

(8 citation statements)

References 16 publications

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“…In similar experiments with other polycyclic aromatic hydrocarbons, benzanthracene (8.8pM) and benz-[alpyrene (7.9#M) were also ineffective in causing URO accumulation, though they induced ethoxyresorufin de-ethylase to high activities (44 and 52pmol of resorufin/min per mg of protein respectively). f-Naphthoflavone (15pM) induced this activity to 125 units, but unexpectedly caused a partial change in porphyrin composition (45% URO, 29% PROTO) as had been noted by Debets et al (1981). None of these polycyclic hydrocarbons, at their maximally effective concentrations, IMCI (nNO) Fig.…”

Section: Assay Of Decreased Uroporphyrinogen Decarboxylase In Intact mentioning

confidence: 70%

Inhibition of uroporphyrinogen decarboxylase by halogenated biphenyls in chick hepatocyte cultures. Essential role for induction of cytochrome P-448

Sinclair¹,

Bement²,

Bonkovsky³

et al. 1984

Biochemical Journal

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Uroporphyrinogen decarboxylase (EC 4.1.1.37) activity was assayed in cultures of chick-embryo hepatocytes by the changes in composition of porphyrins accumulated after addition of excess 5-aminolaevulinate. Control cells accumulated mainly protoporphyrin, whereas cells treated with 3,4,3',4'-tetrachlorobiphenyl or 2,4,5,3',4'-pentabromobiphenyl accumulated mainly uroporphyrin, indicating decreased activity of the decarboxylase. 3-Methylcholanthrene and other polycyclic-hydrocarbon inducers of the P-448 isoenzyme of cytochrome P-450, did not affect the decarboxylase in the absence of the biphenyls. Induction of P-448 was detected as an increase in ethoxyresorufin de-ethylase activity. Pretreatment of cells with methylcholanthrene decreased the time required for the halogenated biphenyls to inhibit the decarboxylase. The dose response of methylcholanthrene showed that less than 40% of the maximal induction of cytochrome P-448 was needed to produce the maximum biphenyl-mediated inhibition of the decarboxylase. In contrast, induction of the cytochrome P-450 isoenzyme by propylisopropylacetamide had no effect on the biphenyl-mediated decrease in decarboxylase activity. Use of inhibitors of the P-450 and P-448 isoenzymes (SKF-525A, piperonyl butoxide and ellipticine) supported the concept that only the P-448 isoenzyme is involved in the inhibition of the decarboxylase by the halogenated biphenyls. The effect of preinduction with methylcholanthrene to enhance inhibition of the decarboxylase was also shown by the increased rate at which porphyrin accumulated from endogenously synthesized 5-aminolaevulinate after treatment of cells with the combination of propylisopropylacetamide and the biphenyls. Antioxidants, chelators of iron, and chromate affected the decrease in decarboxylase activity only if they prevented the induced increase in cytochrome P-448. We conclude that the P-448 and not the P-450 isoenzyme of cytochrome P-450 plays an obligatory role in the inhibition of uroporphyrinogen decarboxylase caused by halogenated biphenyls.

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Section: Assay Of Decreased Uroporphyrinogen Decarboxylase In Intact mentioning

confidence: 70%

Inhibition of uroporphyrinogen decarboxylase by halogenated biphenyls in chick hepatocyte cultures. Essential role for induction of cytochrome P-448

Sinclair¹,

Bement²,

Bonkovsky³

et al. 1984

Biochemical Journal

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“…The liver was removed, rinsed in physiological saline solution, and weighed. Parts of the liver were frozen in liquid nitrogen and stored at -700C until cytochrome (49), using an acid-ethanol solution of chloranil (2,3,5,6-tetrachloro-1 ,4-benzoquinone) and 100-pl samples of whole total-liver homogenate, prepared as described earlier (26). Fluorescence was measured in 96well multiplates at Xex 409 nm and kem 645 nm using a cytofluor multiwell plate reader (Millipore B.V., Etten-Leur, the Netherlands) and coproporphyrin III as a standard.…”

Section: Methodsmentioning

confidence: 99%

Synergistic effect of 2,2',4,4',5,5'-hexachlorobiphenyl and 2,3,7,8-tetrachlorodibenzo-p-dioxin on hepatic porphyrin levels in the rat.

Birgelen

Fase

Kolk

et al. 1996

Environ Health Perspect

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We studied the effect of polychlorinated biphenyls (PCBs) on hepatic porphyrin accumulation in female Sprague-Dawley rats by feeding them diets containing 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153), 2,3,3',4,4',5-hexachlorobiphenyl (PCB 156), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), or combinations of the single PCB congeners with TCDD for 13 weeks. A dose-dependent increase in hepatic porphyrin accumulation occurred after TCDD, PCB 126, or PCB 156 administration, reaching maximal levels of about twice control values. The lowest dose levels for which a significant increase in hepatic porphyrin accumulation was found were 0.7 microgram TCDD/kg diet, 50 micrograms PCB 126/kg diet, or 6 mg PCB 156/kg diet. These doses are equivalent to 47 ng TCDD/kg/day, 3.2 micrograms PCB 126/kg/day, and 365 micrograms PCB 156/kg/day. Relative potencies for hepatic porphyrin accumulation, using TCDD as a reference, ranged from 0.015 to 0.06 for PCB 126 and from 0.0001 to 0.0003 for PCB 156. CYP1A2 activities significantly correlated with hepatic porphyrin levels, with coefficients of 0.629, 0.483, or 0.808 for TCDD, PCB 126, or PCB 156, respectively. Administration of PCB 153 alone did not result in hepatic porphyrin accumulation. Co-administration of PCB 153 and TCDD revealed a strong synergistic effect on porphyrin accumulation (about 800 times control levels). This synergistic effect was significant in rats fed diets containing any combination of PCB 153 with TCDD. Uroporphyrin III and heptacarboxylic porphyrin were accumulated in porphyrinogenic livers. These results suggest that TCDD induction of CYP1A2 may be involved, leading to oxidation of uroporphyrinogen III to uroporphyrin III, in combination with an increase in delta-aminolevulinic acid synthetase induced by PCB 153. Under porphyrinogenic conditions, an inhibitor of CYP1A2 activity may also be formed. The interactive effects on porphyrin accumulation after co-administration of dioxinlike and non-dioxinlike compounds may have significant implications for the risk assessment of these chemicals.ImagesFigure 1.Figure 1.Figure 1.Figure 2.

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“…In addition, following induction, these compounds could be metabolized by the cytochromes P-450 (448) associated with the Ah locus. Debets et al (1980Debets et al ( , 1981 suggested that a reactive metabolite of the PHAs, possibly formed by action of cytochrome P-448, might be capable of binding to some constituent of the heme biosynthesis pathway (such as uroporphyrinogen decarboxylase) leading to the eventual production of porphyria.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have indicated that metabolism of HCB by hepatic cytochrome P-450 mixed-function oxidases (MFC's) is important to its subsequent toxicity (Debets et al, , 1981Elder, 1978;Grant et al, 1974;Kerklaan et al, 1979;Puzynska et al, 1979;Strik et al, 1980). One major difficulty that has been consistently encountered during laboratory studies of HCB and other polyhalogenated aromatics (PHAs) is the tendency of these compounds to produce PCT in mammals only following repeated and prolonged exposure.…”

Section: Introductionmentioning

confidence: 99%

A comparison of the effects of hexachlorobenzene, β‐naphthoflavone, and phenobarbital on cytochrome p‐450 and mixed‐function oxidases in Japanese quail

Carpenter

Williams

Buhler

1985

Journal of Toxicology and Environmental Health

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Hexachlorobenzene (HCB), beta-naphthoflavone (BNF), or phenobarbital (PB) was administered to Japanese quail to determine their effects on hepatic porphyrin levels and drug-metabolizing enzymes. While HCB increased porphyrin levels, PB slightly reduced them, and BNF had no effect. HCB was an excellent inducer in quail, increasing the specific content of cytochrome P-450 to levels similar to those produced by BNF. Additional similarities between HCB- and BNF-treated quail included a comparable hypsochromic absorption shift in the CO-reduced difference spectra of cytochrome P-450 and similar effects on the activities of cytosolic glutathione S-transferase (GSH-t), biphenyl hydroxylase (BPH), and ethoxyresorufin O-deethylase (EROD). However, a differential response to HCB and BNF treatment was seen in the activities of hepatic NADPH-cytochrome P-450 reductase, epoxide hydrolase, GSH-t (microsomal), aryl hydrocarbon hydroxylase (AHH), and ethoxycoumarin O-deethylase (ECOD). The activities of NADPH-cytochrome P-450 reductase, AHH, and ECOD following treatment with HCB were similar to those found after dosing with PB. HCB caused a pattern of induction that was distinct from either BNF or PB and appeared to be a "mixed-type" inducer. The rapidity of the HCB-induced porphyrogenic response of Japanese quail, as compared to mammals, may provide unique advantages for making correlations between the in vivo metabolism of haloaromatic hydrocarbons and their effects on porphyrin metabolism.

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Biotransformation and porphyrinogenic action of hexachlorobenzene and its metabolites in a primary liver cell culture

Cited by 36 publications

References 16 publications

Inhibition of uroporphyrinogen decarboxylase by halogenated biphenyls in chick hepatocyte cultures. Essential role for induction of cytochrome P-448

Inhibition of uroporphyrinogen decarboxylase by halogenated biphenyls in chick hepatocyte cultures. Essential role for induction of cytochrome P-448

Synergistic effect of 2,2',4,4',5,5'-hexachlorobiphenyl and 2,3,7,8-tetrachlorodibenzo-p-dioxin on hepatic porphyrin levels in the rat.

A comparison of the effects of hexachlorobenzene, β‐naphthoflavone, and phenobarbital on cytochrome p‐450 and mixed‐function oxidases in Japanese quail

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