• The Korean Journal of Physiology and Pharmacology
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• v.7 no.3
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• pp.157-162
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• 2003

Our earlier studies found a significant correlation between the activities of ranitidine N-oxidation catalyzed by hepatic flavin-containing monooxygenase (FMO) and the presence of mutations in exon 4 (E158K) and exon 7 (E308G) of the FMO3 gene in Korean volunteers. However, caffeine N-1 demethylation (which is also partially catalyzed by FMO) was not significantly correlated with these FMO3 mutations. In this study, we examined another common mutation (V257M) in exon 6 of FMO3 gene. The V257M variant, which is caused by a point mutation (G769A), was commonly observed (13.21% allele frequency) in our subjects (n=159). This point mutation causes a substitution of $Val^{257}$ to $Met^{257}$, with transformation of the secondary structure. The presence of this mutant allele correlated significantly with a reduction in caffeine N-1-demethylating activity, but was not correlated with the activity of N-oxidation of ranitidine. In a family study, the low FMO activity observed in a person heterozygous for a nonsense mutation in exon 4 (G148X) and heterozygous for missense mutation in exon 6 (V257M) of FMO3 was attributed to the mutations. Our results suggest that various point mutations in the coding regions of FMO3 may influence FMO3 activity according to the probe substrates of varying chemical structure that correlate with each mutation on the FMO3 gene.

• 대한임상약리학회:학술대회논문집
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• 1998.12a
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• pp.24-24
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• 1998

• The Korean Journal of Physiology and Pharmacology
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• v.8 no.4
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• pp.213-218
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• 2004

Primary fish-odor syndrome (FOS) is a genetic disorder caused by defective flavin-containing mono-oxygenase 3 gene (FMO3) with deficient N-oxidation of trimethylamine (TMA), causing trimethylaminuria (TMAU). By contrast, secondary FOS can be acquired by decreased FMO activities in patients with chronic liver diseases, but the underlying mechanisms are unknown. In the present study, we examined plasma NOx concentrations and viral DNA contents as well as in vivo FMO activities and their correlations in chronic viral hepatitis (CVH) patients. Plasma concentration of NOx was significantly increased by 2.1 fold $(56.2{\pm}26.5\;vs.\;26.6{\pm}5.4\;{\mu}M,\;p<0.01)$, and it was positively correlated with plasma hepatitis B virus (HBV) DNA contents $(r^2=0.2838,\;p=0.0107)$. Furthermore, the elevated plasma NOx values were inversely and significantly correlated with in vivo FMO activities detected by ranitidine-challenged test $(8.3%\;vs.\;20.0%,\;r^2=0.2109,\;p=\0.0315)$. TMA N-oxidation activities determined in CVH patients without challenge test were also significantly low (73.6% vs. 95.7%, p< 0.05). In conclusion, these results suggested that secondary FOS could be acquired by the endogenously elevated NO in patients with CVH.

• Toxicological Research
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• v.17
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• pp.127-133
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• 2001

Together with cytochrome P450 (CYP), flavin-containing monooxygenase (FMO) present in liver microsomes oxidizes various endogenous and exogenous chemicals. In an effort to determine the human FMO activity, we have developed two non-invasive urine analysis methods using caffeine (CA) and ranitidine (RA) as the probe compounds. As the production of theobromine (TB) and ranitidine N-oxide (RANO) from CA and RA is catalyzed primarily by the hepatic FMO, we have assigned the urinary molar ratios of TB/CA and RA/RANO as the in vivo FMO activity. In 200 age-matched Korean volunteers, the obtained TB/CA ratio ranged from 0.4 to 15.2 (38-fold difference) and the RA/RANO ratio from 5.7 to 27.2 (4.8-fold). The FMO activity of 20's, determined by caffeine metabolism, was the highest (2.5$\pm$l.9) and those of 30's, 40's, 50's, 60's and 70's were 40%, 50%, 24%, 39% and 36% of the 20's, respectively. Intake of grapefruit juice, known to contain flavonoids, inhibited the in vivo FMO (TB/CA) activity by 79%. Addition of the flavonoids like naringin, quercitrin and kaempferol, present in grapefruit juice, to the in vitro microso-mal FMO assay, thiobenzamide S-oxidation, produced 75%, 70% and 60% inhibition, respectively. Obtained Ki values of quercitrin, kaempferol and naringin on the in vitro FMO activity were 6.2, 12.0 and 13.9 $\mu\textrm{M}$, respectively. This suggested that the dose of drug should need to be adjusted to suit the individual FMO activities when the drugs metabolized by FMO are given to patients. As the intake of grapefruit juice has been identified to inhibit the FMO as well as CYP3A4 and lA2 activities, patients taking drugs metabolized by these enzymes should not drink grapefruit juice as the carrier.