Metabolism of toxins and
carcinogens is carried out by large groups of
xenobiotic-metabolizing
enzymes. These
enzymes are generally considered to be required for elimination of
xenobiotics such as drugs, dietary chemicals and
environmental pollutants, and to be required for chemical toxicity and carcinogenicity. An important role for these
enzymes in metabolism of endogenous chemicals has not been established. Mouse lines in which the genes encoding several
xenobiotic-metabolizing
enzymes were knocked out were produced and are being used to determine the role of metabolism in
carcinogenesis, and acute and chronic toxicities in vivo. Mouse lines lacking the P450s
CYP1A1,
CYP1A2, CYP1B1 and
CYP2E1,
microsomal epoxide hydrolase (mEH),
NADPH:
quinone oxidoreductase and the
glutathione S-transferase P1 have no deleterious phenotypes, indicating that these
enzymes are not required for mammalian development and physiological homeostasis. However, when challenged with toxins and
carcinogens, they respond differently from their wild-type (WT) counterparts. For example, mice lacking
CYP1A2 and
CYP2E1 are totally resistant to
acetaminophen-induced hepatotoxicity. Mice lacking CYP1B1 or mEH are less responsive to
tumorigenesis by 7,12-dimethybenz[a]
anthracene. However, CYP1A2-null mice do not significantly differ from WT mice in their response to the hepatocarcinogen
4-aminobiphenyl. These and other studies indicate that the
xenobiotic-metabolism null mice are of great value in the study of the mechanisms of chemical injury.