the slow metaboliser phenotype. Again, functionally significant variants of the rat
Nat1gene have not been identified and ratNat3has only a single reported polymor-
phism (A207S) of uncertain significance (Walraven et al. 2007 ). PolymorphicN-
acetylation has also been described in the Syrian hamster and was attributed to a
nucleotide substitution, resulting in a premature stop codon at amino acid position
243 (R243Stop) (Ferguson et al. 1996 ). Finally, a polymorphism (V231I) has been
identified in theNAT2gene in the rhesus macaque (Macaca mulatta) that results in
alteredN-acetylation activity (Fakis et al. 2007 ). A comprehensive database main-
tainingNATallelic variants for many non-human mammalian species is available
online (http://www.mbg.duth.gr/non-humannatnomenclature/).
2.2.2 UDP-Glucuronosyltransferase 1A in Rats
The Gunn rat is a mutant strain of the Wistar rat, first identified over 60 years ago,
that develops a severe unconjugated hyperbilirubinaemia (jaundice) resulting from
deficient hepatic bilirubin UDP-glucuronosyltransferase (UGT) activity. It has been
used extensively as a model of unconjugated hyperbilirubinaemia in people (par-
ticularly Crigler-Najjar syndrome, type 1), as well as providing an invaluable tool
for UGT enzymology and molecular genetics (Iyanagi et al. 1989 ). In all mamma-
lian and avian species evaluated to date, theUGT1Agene encodes multiple UGT1A
subfamily enzymes through mRNA splicing of different exon 1 regions encoding
the N-terminal half of the enzyme to shared exons 2–5 that encodes the C-terminal
enzyme half. In the Gunn rat (and in some instances of Crigler-Najjar syndrome in
people), there is a single base deletion that introduces an in-frame stop codon in a
common region of theUGT1Agene (Iyanagi et al. 1989 ; Roy-Chowdhury et al.
1991 ). Consequently, all proteins of UGT1A isoforms are truncated, resulting in a
severe phenotype that includes deficient glucuronidation of bilirubin (by the
UGT1A1 isoform) as well as various drugs (Iyanagi et al. 1989 ; Roy-Chowdhury
et al. 1991 ). However, recent work suggests that there is a degree of compensatory
upregulation of other UGTs (especially UGT2B subfamily isoforms that are
encoded by individual genes) and of other drug-metabolising enzymes, including
cytochrome P450s, and therefore detoxification is not as severely impaired as
would be expected (Dietrich et al. 2001 ; Haraguchi et al. 2004 ). Increased adverse
effects of various drugs and intoxicants that are glucuronidated have been studied in
the Gunn rat. An increase in the covalent binding of the carcinogen benzo[a]pyrene
to liver microsomal protein was reported in Gunn rats, presumably because of
deficient glucuronide conjugation of activated metabolites generated by cyto-
chrome P450 (Hu and Wells 1992 ). Similarly, acetaminophen (paracetamol) exerts
greater hepatic and renal toxicity in the Gunn rat, associated with a 72% reduction
in acetaminophen glucuronidation (de Morais and Wells 1989 ). Enhanced toxicity
of irinotecan, which is commonly used in people to treat colon cancer, has also been
observed in Gunn rats compared with Wistar normal rats, associated with decreased
glucuronidation and increased levels of the active metabolite SN-38 (Onoue et al.
2008 ). Most recently, the Gunn rat has served as a useful model for evaluating and
60 C.M. Mosher and M.H. Court