MOUSE DIOXIN-INDUCIBLE CYTOSOLIC ALDEHYDE DEHYDROGENASE-3 - AHD4 CDNASEQUENCE, GENETIC-MAPPING, AND DIFFERENCES IN MESSENGERRNA LEVELS

We have cloned and sequenced the murine AHD4 cDNA encoding the 'Class 3' cytosolic aldehyde dehydrogenase (ALDH-3c). The cDNA is 1722 bp in length, excluding the poly(A+) tail, and has 5' and 3' nontranslated r egions of 174 bp and 186 bp, respectively. AHD4 encodes a protein of 4 53 amino acids, including the first methionine (M(r) = 50 466). The mu rine AHD4 protein is 91% and 80% similar to the rat and human ALDH3c p roteins, respectively, 64% identical to the rat microsomal ALDH 3 prot ein, and < 28% similar to ALDH 'Class 1' and 'Class 2' proteins. Surpr isingly, in contrast to the rat gene that is expressed in both cell cu ltures and the intact liver, the murine Ahd-4 gene is inducible by 2,3 ,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) or benzo[a]pyrene in c ell cultures but not in liver of the intact adult or newborn mouse. So uthern hybridization analysis of mouse DNA probed with the full-length cDNA reveals that the Ahd-4 gene is likely to span less than a total of 15 kb, and was mapped to chromosome (Chr) 11 between the Mgat-1 and Shbg loci by analysis of two multilocus crosses. AHD4 mRNA levels are strikingly elevated in the untreated mouse hepatoma Hepa-1c1c7 mutant line c37 lacking CYP1A1 (aryl hydrocarbon hydroxylase) activity and i n the untreated 14CoS/14CoS mouse cell line having a homozygous deleti on of about 1.2 cM on Chr 7. Our data suggest that the Ahd-4 gene in m urine cell cultures is regulated by three distinct mechanisms: Ah rece ptor-mediated induction by TCDD or benzo[a]pyrene, CYP1A] metabolism-d ependent repression, and Chr 7-mediated putative derepression.