US EPA

2196101 

Journal Article 

Role of cytochrome P-450 in porphyria caused by halogenated aromatic compounds 

Bonkovsky, HL; Sinclair, PR; Bement, WJ; Lambrecht, RW; Sinclair, JF 

1987 

Yes 

Annals of the New York Academy of Sciences
ISSN: 0077-8923
EISSN: 1749-6632 

514 

96-112 

English 

3327440 

10.1111/j.1749-6632.1987.tb48765.x 

WOS:A1987R689500012 

Studies on the role of cytochrome-P450 in porphyria induced by halogenated aromatic compounds (HACs) were summarized. Cultures of White-Leghorn-chick embryo liver cells were incubated with 0.15 millimolar delta-aminolevulinic-acid (ALA) or 1.8 micromolar (microM) 2,4,5,3',4'-pentabromobiphenyl (67888975) (PBBP) for up to 6 hours. The effects on ethoxyresorufin-deethylase (EROD) activity and porphyrin accumulation and composition were determined. Cells exposed to ALA accumulated primarily protoporphyrin whereas those exposed to PBBP accumulated uroporphyrin. Chick liver embryo cells were pretreated with 3-methylcholanthrene (3MC) or propylisopropylacetamide (PIA), a phenobarbital type inducer, followed by 3,4,3',4'-tetrachlorobiphenyl (32598133) (TCB) in the presence or absence of cycloheximide. The effects on uroporphyrin accumulation were determined. Cycloheximide prevented the accumulation of uroporphyrin induced by TCB. When cells pretreated with 3MC were incubated with TCB and cycloheximide, the accumulation of uroporphyrin was not inhibited. Pretreatment with PIA, followed by TCB did not result in uroporphyrin forming. Inhibitors associated with 3MC induction of cytochrome-P450 such as piperonyl-butoxide and ellipticine when added to incubation mixtures containing TCB inhibited accumulation of uroporphyrin. Inhibitors associated with phenobarbital such as 2-diphenyl-2,2-diphenyl-valerate or cimetidine did not inhibit uroporphyrin accumulation. Chick liver embryo cells were treated with 0 or 0.85microM TCB for 4 hours, followed by 30microM piperonyl-butoxide. The effects on heme synthesis from ALA were determined. TCB decreased heme synthesis from ALA, an effect that was reversed by piperonyl-butoxide. The authors conclude that the 3MC inducible isozyme of cytochrome-P450 plays an important part in HAC mediated uroporphyria in chick embryo liver cells.