ABERRANT CYP1A1 INDUCTION - DISCREPANCY OF CYP1A1 MESSENGER-RNA AND ARYL-HYDROCARBON HYDROXYLASE-ACTIVITY IN MUTANT-CELLS OF MOUSE HEPATOMALINE, HEPA-1

We have isolated new benzo[a]pyrene-resistant clones, cl-21 and cl-32, of the mouse hepatoma line, Hepa-l. CYP1A1-dependent aryl hydrocarbon hydroxylase activity is not inducible by 2,3,7,8-tetrachlorodibenzo-p -dioxin or 3-methylcholanthrene in these two cell lines. However, mRNA of CYP1A1 is inducible in cl-21 and cl-32 cells, as in the wild-type cells, in spite of an undetectable level of cytosolic Ah receptor. The cl-21 cDNA of Cyp1a-1 was found to have a single mutation leading to an amino acid substitution from Leu (118) to Arg (118). However, the C YP1A1 protein band was not detected on Western immunoblots. The cDNA o f cl-32 was found to have a single mutation leading to an amino acid c hange from Arg (359) to Trp (359). The presence of the mature protein in cl-32 was confirmed by Western blot analysis. Somatic cell hybridiz ation experiments demonstrated that the phenotype of cl-21 and cl-32 i s recessive and that these clones belong to the same complementation g roup. These data suggest that there may be a non-Ah receptor-mediated mechanism of CYP1A1 induction.