Induction of cytochrome P4501A isozymes by heterocyclic amines and other food-derived compounds.
The cytochrome P-4501A1 and P-4501A2 enzymes are involved in the metabolic activation of a number of environmental precarcinogens including the food-derived heterocyclic amines. These compounds also induce CYP1A activity in rats, a feature they have in common with several of the xenobiotics (most notably benzo[a]pyrene) which are metabolically activated by the cytochrome P-4501A isozymes. Using an in vitro DNA binding assay and an in vivo functional (transactivating) assay, we have found that the cytochrome P-4501A1 induction response produced by the heterocyclic amines is mediated by the intracellular dioxin receptor. In the absence of ligand, the receptor is inactive and does not bind DNA. In this report we demonstrate a correlation between activation of DNA binding activity of the receptor by the heterocyclic amines and their ability to induce transcription from a minimal dioxin-response element-driven promoter construct. However, relatively high doses of these compounds are required to produce these effects. Therefore, despite a relatively high dietary intake of heterocyclic amines as compared to other cytochrome P-4501A1-inducing substances, the heterocyclic amines most probably only play a minor role in the induction of this enzyme activity. In contrast to the heterocyclic amines, indolo derivatives found in cruciferous vegetables exhibit high affinity for the dioxin receptor and represent potent activators of the DNA binding activity of the receptor. The indolo derivatives are therefore likely to have a larger impact than the heterocyclic amines on human CYP1A1 activity.
Kleman
M I
MI
Department of Medical Nutrition, Karolinska Institute, Huddinge University Hospital, Sweden.
Overvik
E
E
Poellinger
L
L
Gustafsson
J A
JA
D000588:Amines / Q000494:pharmacology*; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002460:Cell Line; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004790:Enzyme Induction; D005502:Food; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology; D009153:Mutagens / Q000494:pharmacology*; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D015533:Transcriptional Activation; D014675:Vegetables
D000588:Amines; D002273:Carcinogens; D004268:DNA-Binding Proteins; D006571:Heterocyclic Compounds; D009153:Mutagens; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2