Aryl hydrocarbon hydroxylase 2,3,7,8-TCDD

Janz, D.M. and C.D. Metcalfe. 1991a. Relative induction of aryl hydrocarbon hydroxylase by 2,3,7,8-TCDD and two coplanar PCBs in rainbow trout (Oncorhynchus mykiss). Environ. Toxicol. Chem. 10 917-923. 

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. 

Nessel CS, Amoruso MA, Umbreit TH, et al. 1990. Hepatic aryl hydrocarbon hydroxylase and cytochrome P450 induction following the transpulmonary absorption of TCDD from intratracheally instilled particles. Fundam Appl Toxicol 15 500-509. 

Many of the toxic and biological effects induced by polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) and PCBs such as carcinogenesis, reproductive disturbances and immunotoxic effects are believed to be mediated via the hepatic cytosolic aryl hydrocarbon receptor (Ah receptor) [254,255]. Based on in vitro and in vivo studies, the toxicity of individual organochlorines have been determined relative to 2,3,7,8-tetrachlorodibenzo-p -dioxin (TCDD) and expressed as toxic equivalency factors (TEFs) [254, 256]. In addition to PCDD/F, structurally related PCBs and PCNs bind to the Ah receptor. After binding to the Ah-receptor, the receptor-ligand complex is transferred into the nucleus where it binds to specific DNA sequences and causes transcription of structural genes, which in turn causes synthesis of various cytochrome P4501A1-dependent enzymes such as ethoxyresorufin O-deethylase (EROD) and aryl hydrocarbon hydroxylase (AHH). TEFs for PCNs have been estimated from enzyme-induction assays of EROD and AHH [10, 257] and Luciferase assays in rat cells [12] cf. Table 4. 

The bioavailability of TCDD from soils contaminated in the environment is an important determinant for risk assessment at TCDD contaminated sites. Literature reports indicate significant variation in bioavailability of TCDD from different sites. Soils from two of the major TCDD contaminated sites are compared for toxicity in guinea pigs and induction of aryl hydrocarbon hydroxylase (AHH) in rats. Times Beach, Missouri, soil is toxic and TCDD is highly bioavailable from this soil whereas Newark, New Jersey, soil is relatively non-toxic and has low bioavailability of TCDD. However, AHH induction in rats was approximately identical. These results confirm previous studies on bioavailability from these soils, and suggest that AHH induction may be an unreliable indicator of bioavailability. 

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. 

Rats were dosed with soil suspensions, by gavage, either once or for four consecutive days. Total TCDD dosages administered to rats were either 10 ug TCDD/kg or 40 ug/ TCDD/kg. Rats were sacrificed 24 hours after the final dose, autopsied, and hepatic microsomal fractions were collected. Aryl hydrocarbon hydroxylase (AHH) levels were determined in the microsomes, using the fluorescent assay of the product of the metabolism of benzo(a)pyrene to 3-OH benzo(a)pyrene (16). 

Table III. Induction of Aryl Hydrocarbon Hydroxylase (AHH) by TCDD Contaminated Soils in Rats.

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