2.2 Conjugative Enzymes
2.2.1 N-acetyltransferase in Mice, Rats, Hamsters, Rabbits
and Rhesus Macaques
In humans, slowN-acetyltransferase (NAT) metabolism resulting from polymorph-
isms in theNATgenes has been implicated in adverse reactions to amine drugs such
as isoniazid and procainamide, as well as susceptibility to develop cancer, particu-
larly bladder cancer (Martell et al. 1991 ; Sim et al. 2008 ). Consequently, laboratory
animals, including mice, rats, hamsters, rabbits and rhesus macaque with naturally
occurringNATpolymorphisms have been used to modelNATpolymorphisms in
people to investigate altered risks for drug toxicities and cancer.
Humans have twoNATgenes,NAT1andNAT2, encoding NAT1 withpara-
aminosalicylic acid as the prototypical substrate, and NAT2 with isoniazid as the
prototypical substrate. Polymorphisms in humanNAT2are thought to be res-
ponsible for adverse reactions to the antituberculosis drug, isoniazid (http://N-
acetyltransferasenomenclature.louisville.edu). The number ofNATgenes varies
between species, such that cats only have NAT1 (with very low turnover rates),
dogs and musk shrews (Suncus marinus) completely lackNAT genes (orN-
acetylation activity), while rodents have three genes designatedNat1, Nat2,and
Nat3(Trepanier et al. 1997 ; Trepanier et al. 1998 ; Sim et al. 2008 ). However, it
should be noted that, based on tissue distribution and substrate specificity, murine
Nat1is most homologous to humanNAT2, and murineNat2is most homologous
to humanNAT1(Boukouvala et al. 2002 ). The reason for this somewhat confusing
nomenclature is that the polymorphic murineNat2locus was named after the
polymorphic humanNAT2locus and this nomenclature was maintained despite
subsequent studies demonstrating different substrate specificities (Sim et al. 2008 ).
The functional significance of murineNat3is unclear, as high turnover substrates
for this enzyme have not yet been identified and deletion of theNat3gene in mice
does not significantly alterN-acetylation of a range of substrates (Sugamori et al.
2007 ).
Polymorphic sulfadiazine acetylation was first described in rabbits over 45 years
ago (Frymoyer and Jacox 1963 ) and it was subsequently determined that this was the
result of a deletion ofNAT2(Sasaki et al. 1991 ). Sequencing of the murineNat1and
Nat2genes in phenotyped fast and slowN-acetylator mouse strains identified a N99I
amino acid change in theNat2protein that was associated with slowN-acetylation
(Martell et al. 1991 ; DeLeon et al. 1995 ). No polymorphisms were identified in the
murineNat1gene. The N99I substitution was found to conformationally modify
the Nat2 enzyme with both diminished stability and decreased substrate affinity
(Martell et al. 1991 ; DeLeon et al. 1995 ). Furthermore, this polymorphism was
associated with an increased susceptibility to teratogen-induced cleft lip/palate in
the slow acetylators (Boukouvala et al. 2002 ). In rats, two slow acetylator inbred
strains have been identified, including WKY and NSD strains. Both strains have
the same two amino acid substitutions (V121I and V266I) that likely account for
Comparative and Veterinary Pharmacogenomics 59