CYP1A2(- -) NULL MUTANT MICE DEVELOP NORMALLY BUT SHOW DEFICIENT DRUG-METABOLISM/

Cytochrome P450 1A2 (CYP1A2) is a predominantly hepatic enzyme known t o be important in the metabolism of numerous foreign chemicals of phar macologic, toxicologic, and carcinogenic significance. CYP1A2 substrat es include aflatoxin B-1, acetaminophen, and a variety of environmenta l arylamines. To define better the developmental and metabolic functio ns of this enzyme, we developed a CYP1A2-deficient mouse line hy homol ogous recombination in embryonic stem cells. Mice homozygous for the t argeted Cyp1a2 gene, designated Cyp1a2(-/-), are completely viable and fertile; histologic examination of 15-day embryos, new-born pups, and 3-week-old mice revealed no abnormalities. No CYP1A2 mRNA was detecte d by Northern blot analysis. Moreover, mRNA levels of Cyp1a1, the othe r gene in the same subfamily, appear unaffected by loss of the Cyp1a2 gene. Because the muscle relaxant zoxazolamine is a known substrate fo r CYP1A2, we studied the Cyp1a2(-/-) genotype by using the zoxazolamin e paralysis test: the Cyp1a2(-/-) mice exhibited dramatically lengthen ed paralysis times relative to the Cyp1a2(+/+) wild-type animals, and the Cyp1a2(+/-) heterozygotes showed an intermediate effect. Availabil ity of a viable and fertile CYP1A2-deficient mouse line will provide a valuable tool for researchers wishing to define the precise role of C YP1A2 in numerous metabolic and pharmacokinetic processes.