developing gene therapy methods for the correction of monogenetic disorders
(Miranda and Bosma 2009 ).
2.2.3 UDP-Glucuronosyltransferase 2B2 in Rats
Another example of a rat strain deficient in a glucuronidation activity is the low
androsterone (LA) Wistar rat. This mutant rat strain was identified initially through
demonstration of a masculinised phenotype accompanied by increased levels of the
androgen androsterone resulting from LA glucuronidation activity in the liver. LA
Wistar rats demonstrate approximately 50-fold lower androsterone glucuronidation
by hepatic microsomes, as well as substantially decreased biliary excretion of
exogenously administered androsterone (Corser et al. 1987 ). Subsequent studies
identified UGT2B2 as a major isoform glucuronidating androsterone and other
endogenous androgenic steroids in rat liver (Haque et al. 1991 ). It was subsequently
demonstrated that UGT2B2 mRNA is not present in the liver, and it was determined
that a major portion of the coding region of the gene is deleted (Corser et al. 1987 ;
Homma et al. 1992 ). Similar to Gunn rats, the LA phenotype demonstrates autoso-
mal recessive inheritance and is present with variable incidence in Wistar rat
colonies throughout the world (Matsui and Watanabe 1982 ; Homma et al. 1992 ).
2.2.4 Thiopurine Methyltransferase in Cats, Dogs and Mice
The pharmacogenetics of the thiopurine methyltransferase (TPMT) enzyme has
been extensively studied in people, as this enzyme metabolises a number of
important cancer and immunosuppressant drugs (including 6-mercaptopurine and
azathioprine), and genetic variants causing low enzyme activity enhance adverse
drug effects such as bone marrow toxicity (Kidd et al. 2004 ; Marsh and Van Booven
2009 ). The incidence of TPMT polymorphism is relatively high in humans, with
12% of Whites being heterozygous, and 3% homozygous for alleles that result in
low or absent TPMT activity (Salavaggione et al. 2002 ). In addition to humans,
TPMT activity has been identified in the red blood cells of dogs, cats, horses, rats,
and mice (White et al. 2000 ). Highly variable and/or polymorphic activity has been
described for mice, cats, and dogs (Fig. 5 ). In a study of 177 dogs, there was a 9-fold
range in TPMT activities, with certain breeds having low activities (such as Giant
Schnauzer) while other breeds (such as Alaskan malamute) had relatively high
activities (Kidd et al. 2004 ) suggesting genetic variation as a cause. In another
study, the canine TPMT gene was sequenced and a total of nine polymorphisms
were identified, including six SNPs and three insertion/deletion variants. Six of
these polymorphisms explained 40% of the variance between dogs (Salavaggione
et al. 2002 ). In contrast to dogs and humans, a study of TPMT in cat blood showed
relatively low TPMT activities, likely explaining the sensitivity of cats to thiopur-
ine treatment (Foster et al. 2000 ; White et al. 2000 ). In addition, 31 polymorphisms
Comparative and Veterinary Pharmacogenomics 61