were discovered, with 12 of these accounting for 30% of the total variance in TPMT
activities representing an approximately 10-fold range (Salavaggione et al. 2004 ).
Variability in TPMT activity between inbred mouse strains has served as a
useful model system for studying TPMT (Hernandez et al. 1990 ). C57BL/6J and
AKR/J have been identified as TPMT slow metaboliser strains, while DBA/2J is a
fast metaboliser phenotype (Otterness and Weinshilboum1987a; Otterness and
Weinshilboum1987b). Breeding studies determined that slow TPMT metabolism
is inherited as an autosomal recessive trait. Although it had been initially proposed
that the different murine phenotypes were due to variations in the quantity of TPMT
protein (analogous to human TPMT variation), inter-strain variations appear to be
primarily related to differential mRNA expression (Watters and McLeod 2002 ). A
genetic study of mouse strain crosses identified only two major haplotypes in the
mouseTpmtgene and those haplotypes were highly correlated with TPMT activity
(Watters et al. 2004 ). However, no particular variant could be identified that
explained the phenotype.
2.3 Transporters
2.3.1 P-glycoprotein in Dogs and Mice
Perhaps the best example of clinically important pharmacogenomic variation in
dogs involves the drug transporterP-glycoprotein (P-gp), which is the product of
REC TPMT activity (U/ml RBCs)(^00)
3
6
9
0
5
10
15
20
a
b
c
Canine RBC TPMT
RBC TPMT activity
Cat RBC TPMT Activity
RBC TPMT Activity, Units/ml RBCs
N = 104
Relative Frequency, %
Human RBC TPMT
n = 145
n = 2609
0
10 20 30 40
0
0
8
16
510
80
12
10 20 30 40
Fig. 5Population distributions of red blood cell thiopurine methyltransferase (TPMT) activities
measured in (a) dogs (n¼145), (b) humans (n¼2,609) and (c) cats (n¼104). Dog and human
data from (Salavaggione et al. 2002 ); cat data from (Salavaggione et al. 2004 )
62 C.M. Mosher and M.H. Court