Genetic polymorphism of cytochrome P-450-dependent phencyclidine hydroxylation in mice. Comparison of phencyclidine hydroxylation in humans.
A mouse model of P-450 phencyclidine 3-cyclohydroxylase (P-450 PCP 3-cyclohydroxylase) genetic polymorphism is described. Up to a 3-fold difference was observed in the constitutive liver microsomal activity of P-450 PCP 3-cyclohydroxylase between "slow" (A/J and DBA/2J) and "rapid" (C57BL/6J and BALB/CJ) phencyclidine (PCP) metabolizers. The segregation of slow and rapid hydroxylator phenotypes between 17 recombinant inbred mouse strains derived from A/J and C57BL/2J mice suggests control of the activity by a single gene located on the X-chromosome or, less likely, on chromosome 17. A liver deficiency of P-450 PCP 3-cyclohydroxylase was observed in the New Zealand rabbit and Wistar rat, as well as in some human subjects. Any relationship of P-450 PCP 3-cyclohydroxylase polymorphism to other well characterized P-450 polymorphisms in mice (aryl hydrocarbon hydroxylase and coumarin hydroxylase) was excluded on the basis of differences in inducibility and activity distribution among the inbred mouse strains. Lack of relationship to the P-450 debrisoquine hydroxylase was confirmed by direct comparison of both activities in the same mouse and human liver microsomes. The pharmacological consequence of the observed polymorphism in mice appears to be that the rapid PCP metabolizers are more resistant to the effects of PCP compared to the slow metabolizers as based upon its ED50 and duration of action in A/J and C57BL/6J mice. The relevance of this data to humans remains to be determined, but clearly the latter show marked differences in PCP 3-cyclohydroxylase activity, which separate into low, intermediate, and high groups.
Holsztynska
E J
EJ
Department of Pharmacology, University of Michigan Medical School, Ann Arbor.
Weber
W W
WW
Domino
E F
EF
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003647:Debrisoquin / Q000378:metabolism; D005260:Female; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D010622:Phencyclidine / Q000378:metabolism* / Q000494:pharmacology; D010641:Phenotype; D011110:Polymorphism, Genetic; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D003577:Cytochrome P-450 Enzyme System; D010622:Phencyclidine; D003647:Debrisoquin