Comparison of levels of aldehyde oxidase with cytochrome P450 activities in human liver in vitro.
Microsomal suspensions and 9000 g supernatant (S-9) fractions were prepared from the liver tissue of six human multiorgan donors. The S-9 fractions were characterized for cytosolic aldehyde oxidase (AO) activity, using three different substrates [N1-methylnicotinamide (NMN), benzaldehyde and 6-methylpurine]. In addition, human liver NMN oxidase activity was compared with that detected in rat, dog and monkey liver S-9 fractions. As expected, the rank order of NMN oxidase activity was monkey > rat > dog, and in five out of six subjects the activity was lowest in humans (< 2.0 nmol/min/mg). The variation in AO activity among the various human livers was greater for NMN oxidase (> 40 fold) than for 6-methylpurine and benzaldehyde oxidase (< or = 3.6 fold) activity. The corresponding microsomal preparations were characterized with respect to the levels of total cytochrome P450 (CYP) and six CYP-dependent mixed-function monooxygenase (MFO) activities. The variation was greatest for dextromethorphan O-demethylase (CYP2D6) and lowest for N,N-dimethylnitrosamine N-demethylase (CYP2E1) activity (147- vs. 1.4-fold). The inter-sample variation for the total CYP, CYP3A (erythromycin N-demethylase), CYP1A2 (7-ethoxyresorufin O-deethylase), CYP2A6 (coumarin 7-hydroxylase) and CYP2C9/10 (tolbutamide 4-methyl hydroxylase) was 2.2- to 5.3-fold. Furthermore, the levels of AO activity did not correlate with total (spectrally detectable) CYP or any of the CYP form-selective MFO activities.
Rodrigues
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Drug Metabolism Department, Abbott Laboratories, Abbott Park, IL 60064.
D000328:Adult; D042931:Aldehyde Oxidase; D000445:Aldehyde Oxidoreductases / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*
D003577:Cytochrome P-450 Enzyme System; D000445:Aldehyde Oxidoreductases; D042931:Aldehyde Oxidase