Abstract
Previous enzymatic and immunological studies from this laboratory have indicated a critical role for cytochrome P450IA2-catalyzed uroporphyrinogen oxidation in the development of uroporphyria caused by halogenated aromatic hydrocarbons. To extend these studies, we investigated whether primary cultures of mammalian hepatocytes which are inducible for cytochrome P450IA2 are also inducible for chemically mediated uroporphyria. Hepatocytes were isolated from C57BL/6 mice and maintained on Matrigel, an extracellular matrix isolated from a mouse tumor. When these cultures were treated with 3,4,5,3',4',5'-hexachlorobiphenyl (HCB) and 5-aminolevulinic acid (ALA), they accumulated cytochrome P450IA2 as well as uroporphyrin (URO) and heptacarboxyporphyrin for up to 12 days. Cultures treated with ALA alone accumulated no P450IA2 and very little URO. Neither URO accumulation nor the level of P450IA2 was affected by addition of iron as the nitrilotriacetate complex. Other inducers of P450IA2 in vivo (3,4,5,3',4'-pentachlorobiphenyl, 3,4,3',4'-tetrachlorobiphenyl, and 3-methylcholanthrene) also increased P450IA2 in the cultures and caused URO accumulation in the presence of added ALA. The tetrachlorobiphenyl and methylcholanthrene caused the...Continue Reading
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