Advances in molecular biology and pharmacogenetics has enabled more com-
prehensive data to be obtained in the face of more protean situations, due to the
multiplicity of species, the multiplicity of breeds within each species with possible
polymorphism and the lack of catalytic specificity of cytochrome P450 isoforms.
For a recent comprehensive review, see Fink-Gremmels ( 2008 ).
The CYP450 system is complex and CYP members are subdivided into families
and sub-families. The naming of CYP enzymes should now follow the system based
on DNA sequencing; therefore the naming based on catalytic activity or substrate
specificity should be avoided once the gene has been cloned (Cribb 2003 ). Practi-
cally, there are 3 CYP families involved in drug metabolism: CYP1, CYP2 and
CYP3 families. The naming system consists of adding an Arabic number for a
family (requiring 40% identity of amino acid sequence as CYP1, CYP2 or CYP3).
For a sub-family (requiring 40–80% identity) a letter is added (A, B, C...), e.g.
CYP1A, CYP1B. Finally, an additional Arabic number is added to identify individ-
ual members of a sub-family (as an isoform) like for CYP1A2 or CYP3A4 etc.
It should be stressed that a completely named CYP enzyme can only be found in
one species because a given amino acid sequence can only derive from one species.
For example CYP3A4 can only be found in humans while the ortholog (compara-
ble) enzyme in the dog is CYP3A12. This naming system based on sequences
homology offers the advantage of being unequivocal but it may render difficult the
presentation of interspecies variability in drug metabolism. Indeed, even if CYP
families share general sequence properties, there exist considerable differences
within a given family in terms of substrate specificity and of enzyme regulation
(induction, inhibition). Thus, it is possible to identify two very similar (ortholog)
CYP enzymes in two different domestic species (in term of amino-acid sequence)
but having very different substrate (biotransformation) specificities. Conversely, a
given drug (substrate) may be metabolisedin vivoby two or more unrelated
(different families) CYP enzymes leading to a multiplicity of substrate/enzyme
combinations. This makes species extrapolation of CYP450 specificity very diffi-
cult. For example, a comparison of the cDNA homologies showed a particularly
high homology between human and pig CYP3A enzymes. However, the response to
chemical inducers varied: rifampicin is an inducer of the nuclear factor PXR in both
human and pig hepatocytes, whereas dexamethasone, which is also an inducer in
man failed to induce testosterone 6b -hydroxylation and midazolam-4-hydroxy-
lation in pig hepatocytes (Monshouwer et al. 1998 ; Lu and Li 2001 ).
An additional complication is that some CYPs are subject to considerable intra-
species variability as a result of both environmental and genetic factors. Polymor-
phism within a given species is a challenge to defining general guidelines for a given
species. A single amino-acid change resulting from a single nucleotide change can
markedly modify the functional properties of the enzyme (expression and substrate
specificity). Although it is expected that these types of polymorphisms may exist in
all animal species, they have not yet been investigated in detail. Polymorphic
differences exist in certain breeds of dogs. For example, beagles have been shown
to have a significantly greater propofol hydroxylase activity than greyhounds (Court
et al. 1999 ), due to a high CYP2B11 activity. Greyhounds also had a much slower
Species Differences in Pharmacokinetics and Pharmacodynamics 39