of genes including those encoding oxidative enzymes (such as CYP1A1) and
conjugative enzymes (such as UGT1A6) (Poland et al. 1994 ). In mice and rats,
theAhgene which encodes for AhR has several known alleles that affect its
responsiveness to dioxins. In mice, there are four alleles,Ahb^1 ,Ahb^2 ,Ahb^3 ,
andAhd, of which the first three display high ligand affinity and differ only by a few
point mutations in the common open reading frame and additional sequence at the
carboxyl ends (Poland and Glover 1990 ). In contrast, theAhdallele encodes the
receptor with the lower binding affinity, attributable to valine at position 375
(Poland et al. 1994 ). The aromatic hydrocarbon responsiveness is inherited as an
autosomal dominant trait and the alleles were named for the mice initially found to
carry them (Ahbfor C57BL/6 mice, andAhdfor DBA/2 mice). It is now known that
AKR, DBA/2 and 129 strains carry theAhdallele, C57BL/6, C58 and MA/My
strains carry theAhb^1 allele, theAhb^2 allele is found in BALB/cBy, A and C3H
strains, while theAhb^3 allele is found inMus caroli, Mus spretusand MOLF/Ei
(Poland and Glover 1990 ). In rats, there is at least a 1,000-fold difference in
sensitivity to the lethal effects of dioxins between the sensitive Long–Evans
(L–E) strain and the resistant Han/Wistar (H/W) strain resulting from a point
mutation in the H/WAhrallele that forms an abnormal C-terminus transactivation
domain and a smaller AhR protein (Simanainen et al. 2003 ). In addition to the
mutation, L–E rats appear to have higher total hepatic levels of AhR than H/W rats
(Pohjanvirta et al. 1999 ).
3 Drug Effect
3.1 Malignant Hyperthermia in Pigs, Dogs, Cats and Horses
Malignant hyperthermia is a heritable drug hypersensitivity syndrome that classi-
cally displays as muscle rigidity, elevated core body temperature, hypercapnia,
acidosis, hyperkalaemia, sympathoadrenal activation, and rhabdomyolysis after
administration of a triggering agent. This is typically an inhalant anaesthetic and/
or succinylcholine. The biochemical basis for the syndrome involves aberrant
regulation of calcium release from sarcoplasmic reticulum stores within skeletal
muscle. Based upon literature reports, affected species include humans, pigs, dogs,
cats, and horses (reviewed in Brunson and Hogan ( 2004 )).
Pigs have been an invaluable research model of malignant hyperthermia, assist-
ing the discovery of the gene mutations most frequently associated with this
syndrome in humans (MacLennan and Phillips 1992 ). The condition was first
identified in pigs and described as “porcine stress syndrome” (PSS). It is charac-
terised by mortality in a high proportion of animals sent to slaughter, death being
preceded by high body temperatures, blotched skin, and hyperventilation. Those
that survived until slaughter were also more likely to have poor quality unmarket-
able meat (described as “pale-soft-exudative” or PSE pork). Subsequently, it was
66 C.M. Mosher and M.H. Court