Aryl hydrocarbon hydroxylase required

Cytochrome P-U50 in carcinogen metabolism. In spite of the bewildering number of carcinogens involved the important and unifying fact is, that most of the organic carcinogens are not carcinogenic per se, but require metabolic activation in situ by cytochrome P-i 50 mediated aryl hydrocarbon hydroxylase (AHH, also known as BP hydroxylase (EC 1.lU.lit.2)). 

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). 

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. 

Dermal treatment of healthy volunteers with 10% coal tar for 4 days produced an 18-fold induction of CYP1A1 mRNA levels in coal-tar-treated skin (Li et al. 1995). In vitro incubation of DNA with coal tar fume concentrates in the presence of mouse and yeast microsomes expressing various cytochrome P450 isoforms or the aryl hydrocarbon hydroxylase receptor (AHR) demonstrated that coal tar fume condensates require metabolic activation to produce DNA adducts (Genevois et al. 1998). Both the AHR and CYP1A were involved in the metabolism of coal tar fume condensate. It was also shown that the reactive metabolites formed by CYP1A are substrates for microsomal epoxide hydrolase. 

There are all sorts of problems with epoxidation by micro-organisms and in general laboratory chemists prefer to use the Sharpless or Jacobsen epoxidations described in chapter 25. The co-hydroxylase from Pseudomonas oleovorans does epoxidise aryl ethers of allylic alcohols with good selectivity and one product has been used in the synthesis of the (5-blocker metropolol.29 However the organism requires gaseous hydrocarbons as carbon sources and the epoxide products poison it. 

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