Sex and strain differences in hepatic debrisoquine 4-hydroxylase activity of the rat.
Debrisoquine 4-hydroxylase activity in microsomal fractions from liver of DA, Fischer, and Lewis rats has been determined. Activity in DA rats is up to 14-fold lower than in animals from the corresponding sex of the other strains. There is also a major sex difference in debrisoquine 4-hydroxylase activity of all three strains. Kinetic analysis revealed at least two components of activity, even in the liver of female DA rats. Thus, the decreased activity in these animals could not be attributed to the absence of a single isozyme of cytochrome P-450. Michaelis-Menten analysis revealed that both components of activity were impaired in these animals. Debrisoquine 4-hydroxylase activity was inducible by both 3-methylcholanthrene and phenobarbital in DA and Fischer rats. However, in the DA rat, activity was inducible only at higher substrate concentrations (greater than 50 microM). It is concluded that the DA rat differs from other strains in at least three different isozymes of cytochrome P-450 that can catalyze the 4-hydroxylation of debrisoquine. At least one of these is male-specific and at least one is inducible. The DA rat might provide a suitable model in which to predict which substrates might show impaired oxidation in the poor metabolizer phenotype, but studies on the molecular mechanism of the polymorphism in this strain would appear to have doubtful validity for the polymorphism in man.
Kahn
G C
GC
Rubenfield
M
M
Davies
D S
DS
Murray
S
S
Boobis
A R
AR
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D066298:In Vitro Techniques; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D012737:Sex Factors; D013045:Species Specificity
D008748:Methylcholanthrene; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6; C023738:acetanilide hydroxylase; D010634:Phenobarbital