The murine aromatic hydrocarbon responsiveness locus: a comparison of receptor levels and several inducible enzyme activities among recombinant inbred lines.
The aromatic hydrocarbon responsiveness (Ah) locus has been correlated with genetic differences in the risk of drug toxicity, teratogenesis, chemical carcinogenesis, and mutagenesis. Hepatic cytosolic Ah receptor levels, 2-amino-5-chlorobenzoxazole (zoxazolamine) paralysis time following beta-naphthoflavone treatment and aryl hydrocarbon hydroxylase (AHH3, acetanilide 4-hydroxylase (Ac4H), and NAD(P)H:menadione oxidoreductase (NMOR)4, induction by 3-methylcholanthrene were studied in (a) the progenitors C57BL/6J (Ahb/Ahb) and DBA/2J (Ahd/Ahd) and 25 BXD recombinant inbred lines, (b) the progenitors C57BL/6N and C3H/HeN and 14 B6NXC3N recombinant inbred lines, and (c) the progenitors C57BL/6J and C3H/HeJ and 12 BXH recombinant inbred lines. The Ahb phenotype exhibits greater than 5 femtomole receptor/mg of cytosolic protein, less than or equal to 15 minutes zoxazolamine paralysis time, and twofold to 15-fold induction of these three hepatic enzyme activities; the Ahd phenotype exhibits less than or equal to 2 fmol receptor/mg protein, greater than 15 minutes zoxazolamine paralysis time, and less than 30% induction of these three activities. Among the BXD lines but especially among the B6NXC3N and BXH lines, high frequencies of recombination were found; the phenotype of each of the five parameters did not segregate with the phenotype of each of the other parameters in four or more recombinant lines. This report shows for the first time that AHH induction by 3-methylcholanthrene can occur in the Ahd phenotype mouse. These data underline the complexity of this genetic system when genes from C57BL/6 and DBA/2 are combined and particularly when genes from C57BL/6 and C3H/He inbred mouse strains are combined.
Bigelow
S W
SW
Laboratory of Developmental Pharmacology, National Institute of Child Health and Human Development, Bethesda, Md.
Nebert
D W
DW
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001551:Benz(a)Anthracenes / Q000494:pharmacology; D001571:Benzoflavones / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H / Q000235:genetics; D008810:Mice, Inbred C57BL / Q000235:genetics; D008811:Mice, Inbred DBA / Q000235:genetics; D008815:Mice, Inbred Strains / Q000235:genetics*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011808:Quinone Reductases / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000235:genetics*; D015049:Zoxazolamine / Q000494:pharmacology; D019324:beta-Naphthoflavone
D001551:Benz(a)Anthracenes; D001571:Benzoflavones; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D008748:Methylcholanthrene; D019324:beta-Naphthoflavone; D015049:Zoxazolamine; C030935:benz(a)anthracene; D001189:Aryl Hydrocarbon Hydroxylases; C023738:acetanilide hydroxylase; D011808:Quinone Reductases