Metabolism as a prerequisite for the porphyrinogenic action of polyhalogenated aromatics, with special reference to hexachlorobenzene and polybrominated biphenyls (Firemaster BP-6)

Debets, F.M.H.; Hamers, W.J.H.M.B.; Strik, J.J.T.W.A.

doi:10.1016/0020-711x(80)90205-0

Cited by 41 publications

(10 citation statements)

References 16 publications

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“…This synergism was postulated to be due to involvement of a phenobarbital-inducible isoenzyme of cytochrome P-450. In contrast, others had reported that the rate of URO production after treatment of the culture with hexachlorobenzene or mixtures of polybrominated biphenyls was increased by pretreatment of cells with MC orP-naphthoflavone (Debets et al, 1980). These latter two compounds induce an isoenzyme that will be referred to in the present paper as 'cytochrome P-448'.…”

mentioning

confidence: 69%

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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confidence: 69%

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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“…Many PHAs, HCB included, are excellent inducers of cytochrome P-450 and related MFOs (Alvares et al, 1973;Courtney, 1979;Goldstein et al, 1976;Stonard, 1975). The importance of an induction of cytochrome P-450 (P-448 type in particular) enzymes in the development of HCBinduced porphyria was indicated from the work of Debets et al (1980;1981). These workers showed a greatly increased sensitivity of isolated chick-embryo liver hepatocytes to HCB following .pretreatment of the cells with BNF.…”

Section: Discussionmentioning

confidence: 93%

“…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%

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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“…Much of the recent research regarding the porphyrogenic action of HCB has been concerned with the role that metabolism plays in HCBinduced porphyria Debets et al, 1980a;Strik et al, 1980). This line of research has led to the suggestion by some researchers that the generation of a metabolite (or metabolites) is responsible for the inactivation of uroporphyrinogen decarboxylase (Debets et al, 1980a,b;1981 a,b;Koss et al, 1980Koss et al, , 1983.…”

Section: Discussionmentioning

confidence: 98%

“…This disruption is characterized by an increased S-aminolevulinic acid synthetase (ALA-S) activity, a decreased uroporphyrinogen decarboxylase activity (Elder et al, 1976), and ultimately an increased production and excretion of porphyrins. Several recent studies have indicated that the metabolism of HCB is important for its porphyrogenic action Puzynska et al, 1979;Debets et al, 1980aDebets et al, , 1981aCarpenter et al, 1984); however, none of the reported metabolites of HCB are capable of generating porphyria when administered by themselves (Koss et al, 1979Wainstok de Calmanovici and San Martin de Viale, 1980). Surprisingly, two of the major metabolites of HCB, pentachlorophenol (PCP) (Sinclair and Granick, 1974) and pentachlorothiophenol (Koss et al, 1977), can cause elevated porphyrin levels in in vitro hepatic systems to which ALA has been added.…”

Section: Introductionmentioning

confidence: 99%

The effect of tetrachlorohydroquinone on hexachlorobenzene‐induced porphyria in Japanese quail

Carpenter

Harvey

Buhler

1985

Journal of Toxicology and Environmental Health

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Female Japanese quail received either hexachlorobenzene (HCB, 100 mg/kg . d) or tetrachlorohydroquinone (TCHQ, 175 mg/kg . d) for 10 d as a primary treatment. Following this, a secondary treatment of HCB (100 mg/kg . d) or TCHQ (175 mg/kg . d), alone or in combination, was administered for 1, 5, 10 or 15 d. The primary HCB treatment caused elevated delta-aminolevulinic acid synthetase (ALA-S) activities and small increases in porphyrin concentrations. Subsequent treatment of these birds with lactose resulted in no further increases in porphyrins or ALA-S. TCHQ treatment caused increases in porphyrins similar to those seen with continued HCB treatment. Apparently, despite the fact that TCHQ alone had no affect on ALA-S or porphyrin levels, this compound is able, in the presence of elevated ALA levels to cause porphyria. A combination of HCB and TCHQ administered to HCB-pretreated animals caused a more severe porphyria than did follow-up treatment with either HCB or TCHQ alone.

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Metabolism as a prerequisite for the porphyrinogenic action of polyhalogenated aromatics, with special reference to hexachlorobenzene and polybrominated biphenyls (Firemaster BP-6)

Cited by 41 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

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

The effect of tetrachlorohydroquinone on hexachlorobenzene‐induced porphyria in Japanese quail

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