The suncus (Suncus murinus) shows poor metabolic phenotype for trimethylamine N-oxygenation.
In vitro and in vivo N-oxygenation of trimethylamine (TMA) in the suncus (Suncus murinus) was investigated. The N-oxygenation of TMA has been thought to be catalyzed by flavin-containing monooxygenase (FMO). In a previous study, we found that the levels of mRNAs for FMOs were extremely low in the suncus. Thus, we intended to evaluate the capacity of the suncus to N-oxygenate TMA compared to the rat. Eadie-Hofstee plots of the TMA N-oxygenation by suncus liver microsomes showed a biphasic pattern, suggesting that more than two enzymes were involved in this reaction. The low K(m) component in the suncus showed a twofold higher K(m) (55 vs. 31 microM) and a fourfold lower V(max) (0.61 vs 2.5 nmol/min/mg protein) values than those obtained using rat liver microsomes, resulting in a sevenfold lower V(max)/K(m) (11 vs 82 microl/min/mg protein) value. After an intraperitoneal administration of TMA (10 mg/kg body wt), the suncus excreted 39.6% of the dose in 24-h urine as TMA, whereas the rats excreted 6.3%. Metabolic ratio in the TMA N-oxygenation was 1.42 and 0.11 in the suncus and the rat, respectively. These results indicate that the suncus can be an animal model for a poor metabolizer phenotype in TMA metabolism.
Mushiroda
T
T
Laboratory of Drug Metabolism, Hokkaido University, Sapporo, Hokkaido, 060-0812, Japan.
Yokoi
T
T
Takahara
E
E
Nagata
O
O
Kato
H
H
Kamataki
T
T
D000818:Animals; D002849:Chromatography, Gas; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008744:Methylamines / Q000493:pharmacokinetics* / Q000652:urine; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000502:physiology*; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D012788:Shrews / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008744:Methylamines; D010105:Oxygenases; C023336:trimethylamine