Comparative and Veterinary Pharmacology

(Elliott) #1

2.1.2 Cytochrome P450 2D in Rats


Unlike humans, who have only one functional CYP2D subfamily protein (i.e.
CYP2D6), rats have six CYP2D subfamily enzymes, including CYP2D1, 2, 3, 4,
5 and 18. Of these, CYP2D2 may be the most similar to human CYP2D6, based on
sequence homology and the ability to metabolise debrisoquine. The Dark Agouti
(DA) rat has been used as an animal model of the human CYP2D6 PM phenotype,
as this strain of rat metabolises debrisoquine and other CYP2D6 substrates much
slower than other rat strains (including Sprague-Dawley and Wistar) (Schulz-
Utermoehl et al. 1999 ). Over 10 years ago, it was determined that low debrisoquine
metabolism in DA rats was probably the result of low protein levels of CYP2D2 in
the liver (Schulz-Utermoehl et al. 1999 ). More recent studies have demonstrated
lower CYP2D2 mRNA levels (Kawase et al. 2008 ). However, the molecular
genetic cause of this difference is not understood. A polymorphism in diazepam
para-hydroxylation has also been identified in rats with lowest activity in DA rats
compared with Brown Norway, Sprague-Dawley and Wistar strains (Sakai et al.
2009 ). Polymorphism within the Wistar strain was also observed with both EM and
PM phenotypes. A recent study established that this polymorphism is the result of a
nucleotide (thymine) insertion into exon 8 of the CYP2D3 gene, resulting in a
reading frame shift and enzyme protein truncated prior to the critical heme-binding
domain (Sakai et al. 2009 ).


2.1.3 Cytochrome P450 2C41 in Dogs


To date, two members of the CYP2C subfamily have been studied in dogs,
CYP2C21 and CYP2C41. CYP2C21 shares 70% amino acid identity with
CYP2C41 and both are similar to the human CYP2C isoforms expressed in liver,
including CYP2C8, CYP2C9, and CYP2C19 (Shou et al. 2003 ). Of seven different
canine CYPs tested (including CYP2C21 and CYP2C41), canine CYP2C21 was
most active against the human CYP2C9 substrate, diclofenac (Shou et al. 2003 ). On
the other hand, neither of the canine CYP2Cs metabolised the human CYP2C19
substrateS-mephenytoin and CYP2C41 possessed only low activity for all sub-
strates evaluated (Shou et al. 2003 ). Both CYP2C21 and CYP2C41 are expressed in
the canine liver; however, while CYP2C21 mRNA was detected in all nine (100%)
Beagle livers examined, CYP2C41 mRNA was detected only in one of the nine
(11%). A later study confirmed this polymorphism, showing that only 5 of 11 (45%)
canine livers expressed CYP2C41 (Graham et al. 2003 ). The molecular basis for
this polymorphism appears to be deletion of the CYP2C41 gene encompassing at
least exon 4 to exon 7 (Blaisdell et al. 1998 ). Genotyping of dogs indicated
complete concordance between the lack of expression of CYP2C41 mRNA in the
liver and the presence of the CYP2C41 gene deletion. Furthermore, the deletion
was identified in mixed-breed dogs, suggesting that it is not specific to Beagles. It is
not yet clear what impact this polymorphism will have on canine drug metabolism
because high turnover substrates for CYP2C41 have not been identified to date.


Comparative and Veterinary Pharmacogenomics 53

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