STRUCTURAL GENE-PRODUCTS OF THE AH LOCUS - TRANSCRIPTIONAL REGULATION OF CYTOCHROME-P1-450 AND CYTOCHROME-P3-450 MESSENGER-RNA LEVELS BY 3-METHYLCHOLANTHRENE

  • 1 January 1984
    • journal article
    • research article
    • Vol. 26  (1) , 117-121
Abstract
Mouse liver cytochromes P1-450 and P3-450 represent those forms of polycylic hydrocarbon-induced P-450 most closely associated with induced aryl hydrocarbon (benzo[a]pyrene) hydroxylase and acetanilide 4-hydroxylase activity, respectively. These 2 proteins are controlled by the Ah receptor: C57BL/6N mice possess the high-affinity receptor; DBA/2N mice, the poor-affinity receptor. 3-Methylcholanthrene at the highest dose technically possible induces both proteins in C57BL/6N but not DBA/2N mice, whereas sufficiently high doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induce both proteins in both inbred mouse strains. Plasmids containing DNA complementary to P1-450 and P3-450 mRNA, respectively, were used in an in vitro nuclear transcription assay to determine the mechanism of the induction response. In C57BL/6N mice, transcriptional rates of the P1-450 and P3-450 genes increase dramatically as early as 3 h after 3-methylcholanthrene treatment and at 12 h reach maximal levels of 20- and 15-fold, respectively, above control values. In contrast, no increase in either gene is found in 3-methylcholanthrene-treated DBA/2N mice. Following TCDD administration, both P1-450 and P3-450 gene transcription rates are elevated in DBA/2N mice. There is a 3- to 6-h lag period between the early onset of enhanced transcription rates and the later rise in P1-450 and P3-450 mRNA. Basal and induced levels of P3-450 mRNA are about 5-fold greater than those of P1-450 mRNA. The 3-methylcholanthrene and TCDD induction responses, governed by the Ah receptor, evidently are mediated principally through an increase in specific gene transcription.

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