Ah locus

Enzyme Differences. Variation in the nature and amount of constitutively expressed microsomal P450s have not been studied extensively in different strains of the same vertebrate. The only thorough investigations, those of the Ah Locus, which controls aryl hydrocarbon hydroxylase induction, have shown that in addition to quantitative differences in the amount of P450 after induction in different strains of mice, there may also be a qualitative difference in the P450 isozymes induced (see Section 9.5.2). 

Ah locus A gene(s) controlling the trait of responsiveness for induction of enzymes by aromatic hydrocarbons. In addition to aromatic hydrocarbons such as the polycyclics, the chlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls, as well as the brominated biphenyls, are involved. This trait, originally defined by studies of induction of hepatic aryl hydrocarbon hydroxylase activity following 3-methylcholanthrene treatment, is inherited by simple autosomal dominance in crosses and backcrosses between C57BL/6 (Ah-responsive) and DBA/2 (Ah-nonresponsive) mice. 

Ah receptor (AHR) A protein coded for by a gene of the Ah locus. The initial location of the Ah receptor is believed to be in the cytosol and, after binding to a ligand such as TCDD, is transported to the nucleus. Binding of aromatic hydrocarbons to the Ah receptor of mice is a prerequisite for the induction of many xenobiotic metabolizing enzymes, as well as for two responses to TCDD epidermal hyperplasia and thymic atrophy. Ah-responsive mice have a high-affinity receptor, whereas the Ah-nonresponsive mice have a low-affinity receptor. 

Similarly, in vitro studies with lymphocytes, spleen cells, and bone marrow cells from 2,3,7,8-TCDD-pretreated mice indicated that 2,3,7,8-TCDD acts by an Ah locus-dependent mechanism to obstruct the formation of cytotoxic T cell generation from their precursors (Dooley et al. 1990 Holladay et al. 1991 Nagarkatti et al. 1984). A brief summary of the possible mechanisms of 2,3,7,8-TCDD immunotoxicity can be found in Section 2.4.2. 

TCDF resulted in cleft palates and hydronephrosis in the offspring (Hassoun et al. 1984). The results obtained in different strains of mice indicated an association with the Ah locus. Comparable results were obtained previously in mice exposed to 2,3,7,8-TCDD (Abbott and Bimbaum 1989a Abbott et al. 1987a, 1987b Courtney 1976). When C57BL/6N mice were treated orally with 2,3,7,8-TCDD and... 

Bartsch H, Hietanen E, Petruzzelli S, et al. 1990. Possible prognostic value of pulmonary AH-locus-linked enzymes in patients with tobacco-related lung cancer. Int J Cancer 46 185-188. 

Bimbaum LS. 1986. Distribution and excretion of 2,3,7,8-tetrachlorodibenzo-p-dioxin in cogenic strains of mice which differ at the Ah locus. Drug Metab Dispos 14 34-40. 

Kerkvliet NI, Baecher-Steppan L, Smith BB, et al. 1990b. Role of the Ah locus in suppression of cytotoxic T lymphocyte activity by halogenated aromatic hydrocarbons (PCBs and TCDD) ... 

Structure-activity relationships and effects in C57B1/6 mice congenic at the Ah locus. Fundam Appl Toxicol 14 532-541. 

Kerkvliet NI, Steppan LB, Brauner JA, et al. 1990a. Influence of the Ah locus on the humoral immunotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) evidence for Ah receptor-dependent and Ah receptor independent mechanisms of immunosuppression. Toxicol Appl Pharmacol 105 26-36. 

Kouri RE, Rude TH, Joglekar R, et al. 1978. 2,3,7,8-Tetrachlorodibenzo-p-dioxin as cocarcinogen causing 3-methylcholanthrene-initiated subcutaneous tumors in mice genetically "nonresponsive" at Ah locus. Cancer Res 38 2777-2783. 

Poland A, Glover E. 1980. 2,3,7,8-Tetrachlorodibenzo-p-dioxin segregation of toxicity with the Ah locus. Mol Pharmacol 17 86-94. 

Nebert DW, Petersen DD, Puga A. Human AH locus polymorphism and cancer inducibility of CYP1A1 and other genes by combustion products and dioxin. Pharmacogenetics 1991 1 (2) 68—78. 

Nebert DW. The Ah locus genetic differences in toxicity, cancer, mutation, and birth defects. Crit Rev Toxicol 1989 20 153-174. 

Nebert, D.W., M. Negishi, M.A. Lang, L.M. H elmeland, and H.J. Eisen. Hie Ah locus, a multigene family necessary for survival in a chemically adverse environment Comparison with the immune system. 

Nebert. Isolation and characterization of a cloned DNA sequence associated with the murine Ah locus and a 3-methylcholanthrene-induced form of cytochrome P-450. Proc. Natl. Acad. Sci. U.S.A. 78 800-804, 1981. 

Okey, A.B., G.P. Bondy, M.E. Mason, G.F. Kahl, H.J. Eisen, T.M. Guenthner, and D.W. Nebert. Regulatory gene product of the Ah locus. Characterization of the cytosolic inducer-receptor complex and evidence... 

Shum, S., N.M. Jensen, and D.W. Nebert. The Murine Ah locus In utero toxicity and teratogenesis associated with genetic differences in benzo(a)pyrene metabolism. Teratology 20 365-376, 1979. 

Cook, J.C. and Hodgson, E. (1986). Induction of cytochrome P-450 in congeric C57B/6J mite bv isosafrale lack of correlation with the Ah locus. Chem.-Biol, Interact. 58, 23,3-240. 

Hoshino K, Hyashi Y, Takehira Y, et al. 1981. Influences of genetic factors on the teratogenicity of environmental pollutants Teratogenic susceptibility to benzo[a]pyrene and Ah locus in mice. Congenital Anomalies 97-103. 

Lubet RA. Brunda MJ, Lemaire B. et al. 1984. Polycyclic hydrocarbon Induced immunotoxicity in mice Role ofthe Ah locus. In Cooke M, Dennis AJ, eds. Mechanisms, methods and metabolism Polynuclear aromatic hydrocarbons. 8th International Symposium. Columbus. OH Battelle Press, 843- 855. 

Wielgosz SM, Brauze D, Pawlak AL. 1991. Ah locus-associated differences in induction of sister-chromatid exchanges and in DNA adducts by benzo[a]pyrene in mice. Mutat Res 246(1) 129-137. 

Marczylo T, loannides C. 1997. Induction of the rat hepatic cytosolic arylamine oxidase by a series of polychlorinated biphenyls association with the Ah locus. Toxicol Lett 92(2) 81-91. 

---