Q.5 [15 marks] Cytochrome P450 enzymes have evolved to metabolise xenobiotics fr

Question

Q.5 [15 marks]
Cytochrome P450 enzymes have evolved to metabolise xenobiotics from plants or the environment.
a) Explain why dioxin is difficult to metabolise in comparison to medicinal drugs

b) What are the molecular consequences of dioxin infiltration into cells that lead to toxic responses?

c) Outline an in vitro experiment you could carry out to show that Arnt (Aryl hydrocarbon Receptor Nuclear Translocator) is essential for the dioxin receptor to bind to the response element of the Cytochrome P450 1A1 gene.

Explanation / Answer

a)

b)

The mechanism of action by which dioxins exercise their biochemical effects on vertebrate species is through activation of the Aryl hydrocarbon Receptor (AhR), a ligand-activated basic helix-loop-helix transcription factor, and a member of the PER-ARNT-SIM (PAS) superfamily of transcription factors . The AhR is a highly conserved protein across vertebrate species, and related proteins have been identified in invertebrates, such as C. elegans and Drosophila species . A member of the growing PAS family of key regulatory proteins --which are often thought of as “biological sensors” -- the AhR is believed to play key roles in development, aging, hypoxia, and circadian rhythms .

In the cell, in its non-ligand bound state, AhR exists as a cytosolic complex with chaperones, including two molecules of heat shock protein (Hsp) 90, and one molecule each of prostaglandin E synthase 3 (p23) and immunophilin-like protein hepatitis B virus X-associated protein 2 (XAP2, also known as AIP or ARA9) [29]. TCDD enters the cell via diffusion and when it binds AhR, one molecule of Hsp 90, as well as both p23 and XAP2 dissociate from AhR, and the AhR-TCDD complex translocates into the nucleus. Once in the nucleus, AhR must heterodimerize with the AhR nuclear translocator (Arnt), at their respective PAS domains, releasing the remaining molecule of Hsp 90, before transcription can occur. Binding of the AhR-TCDD-Arnt complex to the DNA at dioxin response elements (DRE; or xenobiotic response elements, XRE) in the promoter regions of target genes may then occur – depending upon the co-activators or co-repressors present – and transcription may proceed. E

c) By silencing or mutating gene for expression of ArH.

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