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Species and sex differences in expression of flavin-containing monooxygenase form 3 in liver and kidney microsomes
S L Ripp1, K Itagaki, R M Philpot
1Department of Comparative Biosciences and Environmental Toxicology Center, University of Wisconsin-Madison, 53706, USA.
Abstract:
Flavin-containing monooxygenase (FMO) 3 is the predominant FMO isoform in adult human liver; however, little is known about its expression in common laboratory species. Studies have shown FMO3 levels to be sex-dependent in mouse liver, but not in human liver. The current study was undertaken to determine the expression of FMO3 in liver and kidney microsomes from multiple species, and to determine whether the sex dependence seen in mouse liver extends to other species and/or tissues. FMO3 had previously been shown to be the major FMO involved in methionine S-oxidation in rat and rabbit liver microsomes. In this study, species differences in FMO3 levels were assessed in liver microsomes from humans, rats, dogs, mice, and rabbits, and in kidney microsomes from rats, dogs, mice, and rabbits, by comparing methionine S-oxidase activities. Species differences were noted in male liver microsomes, with rabbits having 3-fold higher methionine S-oxidase activity than mice and dogs and 1.5-fold higher activity than humans and rats. Species differences were also noted in male and female kidney microsomes, with rats exhibiting 2- to 6-fold higher methionine S-oxidase activity than the other species. Sex differences in FMO3 levels were assessed using methionine S-oxidase activity and immunoblotting, and were noted only in liver microsomes from mice and dogs, with females having higher levels than males. Results also show that FMO3 orthologs from multiple species are catalytically similar with regard to methionine, S-allyl-L-cysteine, and S-(1,2-dichlorovinyl)-L-cysteine S-oxidations.
Insights
Flavin-containing monooxygenase 3 (FMO3) expression varies across species and tissues. While sex differences in FMO3 liver levels were observed in mice and dogs, rats showed higher kidney FMO3 activity.
Area of Science:
- Biochemistry
- Pharmacology
- Comparative Physiology
Background:
- Flavin-containing monooxygenase (FMO) 3 is a key enzyme in drug and xenobiotic metabolism, predominantly found in adult human liver.
- Limited data exists on FMO3 expression across common laboratory species, hindering comparative metabolic studies.
- Previous research indicated sex-dependent FMO3 levels in mouse liver, but not human liver.
Purpose of the Study:
- To investigate FMO3 expression in liver and kidney microsomes across multiple species (humans, rats, dogs, mice, rabbits).
- To determine if the observed sex-dependent FMO3 expression in mouse liver is conserved in other species and tissues.
- To compare the catalytic activity of FMO3 orthologs from different species using various substrates.
Main Methods:
- Assessed species and sex differences in FMO3 levels by measuring methionine S-oxidase activity in liver and kidney microsomes.
- Utilized immunoblotting to confirm sex differences in FMO3 expression.
- Compared catalytic activity of FMO3 orthologs using methionine, S-allyl-L-cysteine, and S-(1,2-dichlorovinyl)-L-cysteine as substrates.
Main Results:
- Significant species differences in FMO3 activity were observed in male liver microsomes, with rabbits showing the highest activity.
- Rats exhibited notably higher methionine S-oxidase activity in both male and female kidney microsomes compared to other species.
- Sex differences in FMO3 levels, with females having higher expression, were identified in mouse and dog liver microsomes.
Conclusions:
- FMO3 expression and activity exhibit considerable interspecies and inter-tissue variability.
- Sex-dependent regulation of FMO3 in the liver is not universal across species, being evident in mice and dogs but not humans.
- FMO3 orthologs demonstrate conserved catalytic function across species for the tested S-oxidations, suggesting functional similarity despite expression differences.