Aryl hydrocarbon hydroxylase induction

Cheney, B. V. 1982. Structural Factors Affecting Aryl Hydrocarbon Hydroxylase Induction of Dibenzo-p-Dioxins and Dibenzofurans. Int. J. Quant. Chem. 21,445. 

Janz, D.M. and C.D. Metcalfe. 1991b. Nonadditive interactions of 2,3,7,8-TCDD and 3,3, 4,4 -tctrachIorobi-phenyl on aryl hydrocarbon hydroxylase induction in rainbow trout (Oncorhynchus mykiss). Chemosphere 23 467-472. 

Aryl hydrocarbon hydroxylase induction. Smoke of cured leaf, administered by inhalation to mice and rats at an undiluted concentration, produced an induction in lungs and kidneys. There was no induction in bowels and liver . 

Van Cantfort, J., and J. Gielen. Organ specificity of aryl hydrocarbon hydroxylase induction by cigarette smoke in rats and mice. Biochem Pharmacol 1975 24 1253. 

Robertson LW, Andres JL, Safe SH, et al. 1983a. Toxicity of 3,3, 4,4 - and 2,2, 5,5 -tetrabromobiphenyl correlation of activity with aryl hydrocarbon hydroxylase induction and lack of protection by antioxidants. J Toxicol Environ Health 11 81-91. 

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). 

Perhaps the best understood example of induction involves induction of the aromatic hydrocarbon receptor (AhR) by compounds such as TCDD and 3-methylcholanthrene. The use of suitable inhibitors of RNA and DNA polymerase activity has shown that inhibitors of RNA synthesis such as actinomycin D and mercapto(pyridethyl)benzimida-zole block aryl hydrocarbon hydroxylase induction, whereas hydroxyurea, at levels that completely block the incorporation of thymidine into DNA, has no effect. Thus it appears that the inductive effect is at the level of transcription and that DNA synthesis is not required. 

Denomme MA, Homonoko K, Fujita T, et al. 1985. Effects of substituents on the cytosolic receptor-binding affinities of aryl hydrocarbon hydroxylase induction potencies of 7-substituted 2,3-dichlorodibenzo-p-dioxins. Mol Pharmacol 27 656-661. 

Roberts EA, Johnson KC, Harper PA, et al. 1990. Characterization of the Ah receptor mediating aryl hydrocarbon hydroxylase induction in the human liver cell line HepG2. Arch Biochem Biophys... 

Owens, I.S., and D.W. Nebert. Aryl hydrocarbon hydroxylase induction in mammalian liver-derived... 

Owens, I.S., and D.W. Nebert. Aryl hydrocarbon hydroxylase induction in mammalian liver-derived cell cultures. Stimulation of "cytochrome P1450-ass ocia ted" enzyme activity by many inducing compounds. Mol. Pharmacol. 11 94-104, 1975. 

Bickers DR, Kappas A. 1978. Human skin aryl hydrocarbon hydroxylase induction by coal tar. J Clin Invest 62 1061-1068. 

Cheney BV. Structural factors affecting aryl hydrocarbon hydroxylase induction by dibenzo-/>-dioxins and dibenzofurans. Int J Quantum Chem 1982 21 445 -63. 

McConnell et al (8) studied the bioavailability of TCDD from the dioxin contaminated soils at Times Beach, Missouri. They reported a bioavailability (based on toxicity data and aryl hydrocarbon hydroxylase induction) of approximately 60-85% from soil from Times Beach, Missouri. Lucier et al ( ) examined the same Missouri soils as reported by McConnell et al Using AHH induction in rat liver as a measure, they estimated that TCDD was about 25-50% bioavailable from these soils. These data demonstrated a clear dose response for TCDD toxicity and AHH induction from the contaminated soils. 

Gielen, J.E., EM. Goujon, and D.W. Nebert (1972). Genetic regulation of aryl hydrocarbon hydroxylase induction. J. Biol. Chem. 247, 1125-1137. 

Thomas, P.E., R.E. Kouri, and J.J. Hutton (1972). The genetics of aryl hydrocarbon hydroxylase induction in mice A single gene difference between C57BL/6J and DBA/2J. Biochem. Genetics 6, 157-168. 

Nebert, D.W., EM. Goujon, and J.E. Gielen (1972). Aryl hydrocarbon hydroxylase induction by polycyclic hydrocarbons Simple autosomal dominant trait in the mouse. Nat. New Biol. 236, 107. 

Levitt, R.C., C. LeGraverene, D. Nebert, and O. PeUconnen Effects of harmane and norharmane on the mutagenicity and binding to DNA of benzo[a]pyrene metabolites in vitro and on aryl hydrocarbon hydroxylase induction in cell culture Biochem. Biophys. Res. Comm. 79 (1977) 1167-1175. 

A. E rkinson and S. Safe, Aryl hydrocarbon hydroxylase induction... 

J. R. Robinson and D. W. Nebert, Genetic expression of aryl hydrocarbon hydroxylase induction Presence or absence of association with zoxazolamine, diphenylhydantoin, and hexobarbital metabolism. Mol. Pharmacol. 10, 484-493 (1974). 

Induction of aryl hydrocarbon hydroxylase activity in tele-ost fish (28, 1+1+) and elasmobranch (25.) has also been observed without a hypsochromic shift in the spectrum of the cytochrome P-1+50. CO complex. 

Lin, W.S. and Kapoor, M. Induction of aryl hydrocarbon hydroxylase in Neurospora crassa by benzol a] pyrene, Curr. Microbiol, 3 177-180, 1979. 

No studies were located regarding the metabolic pathway of fuel oils in humans. In one animal study, fuel oil no. 2 applied to the skin of rats induced cutaneous aryl hydrocarbon hydroxylase activity in rat skin microsomal preparations by causing a three-fold induction of benzo(a)pyrene (BaP) 3-hydroxylase activity (Rahimtula et al. 1982). In addition, BaP 3-hydroxylase activity was selectively inhibited by -naphthoflavone, but not by metyrapone, suggesting that cytochrome P-448 enzymes are induced and may participate in the metabolism of this fuel oil (Rahimtula et al. 1982). 

Nebert, D.W. and Bausserman, L.L. (1970). Fate of inducer during induction of aryl hydrocarbon hydroxylase activity in mammalian cell culture. II. Levels of intracellular content of polycyclic hydrocarbon during enzyme induction and decay ) Mol. Pharmacol 6,304. 

The induction of the CYPs has been demonstrated in many different species including humans, and in various different tissues as well as the liver. Induction usually results from repeated or chronic exposure, although the extent of exposure is variable. The result of induction is an increase in the amount of an enzyme induction requires de novo protein synthesis, and therefore an increase in the apparent metabolic activity of a tissue in vitro or animal in vivo. Consequently, inhibitors of protein synthesis, such as cycloheximide, inhibit induction. It is a reversible cellular response to exposure to a substance. Thus, it can be shown in isolated cells, such as hamster fetal cells in culture, that exposure to benzo[a]anthracene induces aryl hydrocarbon hydroxylase (AHH) activity (CYP1A1). 

Mechanism and Genetics of Induction in Mammals. Many different mechanisms may be involved in CYP induction. These include increased transcription of DNA, increased mRNA translation to protein, mRNA stabilization, and protein stabilization. Induction can only occur in intact cells and cannot be achieved by the addition of inducers directly to cell fractions such as microsomes. It has been known for some time that in most cases of increase in monooxygenase activity there is a true induction involving synthesis of new enzyme, and not the activation of enzyme already synthesized, since induction is generally prevented by inhibitors of protein synthesis. For example, the protein synthesis inhibitors such as puromycin, ethionine, and cyclo-heximide inhibit aryl hydrocarbon hydroxylase activity. A simplified scheme for gene expression and protein synthesis is shown in Figure 9.7. 

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. 

Bradlaw JA, Garthoff LH, Hurley NE, et al. 1980. Comparative induction of aryl hydrocarbon hydroxylase activity in vitro by analogs of dibenzo-p-dioxin. Food Cosmet Toxicol 18 627-635. 

Harris M, Piskorska-Pliszczynska J, Zacharewski T, et al. 1989a. Structure-dependent induction of aryl hydrocarbon hydroxylase in human breast cancer cell lines and characterization of the Ah receptor. 

Jones KG, Sweeney GD. 1977. Association between induction of aryl hydrocarbon hydroxylase and depression of uroporphyrinogen decarboxylase activity. Res Commun Chem Pathol Pharmacol 17 631-637. 

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