title: Formation of zinc protoporphyrin in cultured hepatocytes: effects of ferrochelatase inhibition, iron chelation or lead.
abstract: The formation of zinc protoporphyrin in response to lead or iron depletion has previously been investigated in erythroid systems. Because of its possible metabolic role in non-erythroid tissue, we investigated the formation of zinc protoporphyrin in cultured hepatocytes. The effects of lead and inhibitors of ferrochelatase, the iron insertion step of heme synthesis, on the conversion of 5-aminolevulinic acid to zinc protoporphyrin, protoporphyrin and heme were compared in rat and chick embryo hepatocyte cultures. In rat cultures, zinc protoporphyrin was synthesized enzymatically by ferrochelatase, since N-methylmesoporphyrin, an inhibitor of ferrochelatase. caused 40% or greater decreases in both heme and zinc protoporphyrin accumulation and markedly stimulated protoporphyrin accumulation. In addition, chelation of ferrous iron with 2,2'-dipyridyl decreased heme accumulation by 50%, but increased ZPP accumulation by 200%. Zinc protoporphyrin formation in chick embryo hepatocytes required the addition of zinc as well as 5-aminolevulinic acid and apparently was non-enzymatic, since it was not inhibited by N-methylmesoporphyrin nor increased by iron chelation. In the presence of 5-aminolevulinic acid, lead had no effect on zinc protoporphyrin, protoporphyrin or heme accumulation in chick hepatocytes, but decreased all three in rat hepatocytes, with the decrease in protoporphyrin being far greater than that of zinc protoporphyrin or heme. These findings indicate that, in contrast to the effect of lead in erythroid tissue, it did not specifically increase zinc protoporphyrin accumulation or alter iron availability in cultured hepatocytes.
authors.affiliation: Department of Microbiology, Dartmouth Medical School, Hanover, NH 03755, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Jacobs
authors.forename: P R
authors.initials: PR
authors.lastname: Sinclair
authors.forename: J F
authors.initials: JF
authors.lastname: Sinclair
authors.forename: N
authors.initials: N
authors.lastname: Gorman
authors.forename: H S
authors.initials: HS
authors.lastname: Walton
authors.forename: S G
authors.initials: SG
authors.lastname: Wood
authors.forename: C
authors.initials: C
authors.lastname: Nichols
mesh_terms: D000622:Aminolevulinic Acid / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005294:Ferrochelatase / Q000037:antagonists & inhibitors*; D006418:Heme / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007854:Lead / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011524:Protoporphyrins / Q000096:biosynthesis* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D004791:Enzyme Inhibitors; D007502:Iron Chelating Agents; D011524:Protoporphyrins; C017803:zinc protoporphyrin; D007854:Lead; D006418:Heme; D000622:Aminolevulinic Acid; D005294:Ferrochelatase