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Biomedical subjects

John R Cashman

Publications and source records attributed to John R Cashman.

At least 19 recordsLinked to original sources
PubMed2006

Effect of genetic variants of the human flavin-containing monooxygenase 3 on N- and S-oxygenation activities.

The decreased capacity of the flavin-containing monooxygenase 3 (FMO3) to oxygenate xenobiotics including trimethylamine is believed to contribute to metabolic disorders. The aim of this study was to functionally characterize FMO3 variants recently found in a Japanese population and compare them with selective functional activity of other FMO3 variants. Recombinant Glu158Lys and Glu158Lys-Glu308Gly FMO3 expressed in Escherichia coli membranes showed slightly decreased N-oxygenation of benzydamine and trimethylamine. Selective functional S-oxygenation of these variants by methyl p-tolyl sulfide or sulindac sulfide was comparable to that of wild-type FMO3. The Glu158Lys-Thr201Lys-Glu308Gly and Val257Met-Met260Val variants showed significantly decreased oxygenation of typical FMO3 substrates (i.e., approximately one-tenth of the V(max)/K(m) values). Val257Met FMO3 had a lower catalytic efficiency for methyl p-tolyl sulfide and sulindac sulfide S-oxygenation. However, compared with wild-type FMO3, Val257Met FMO3 showed a similar catalytic efficiency for N-oxygenation of benzydamine and trimethylamine. The catalytic efficiency for benzydamine and trimethylamine N-oxygenation by Arg205Cys FMO3 was only moderately decreased, but it possessed decreased sulindac sulfide S-oxygenation activity. Kinetic analysis showed that Arg205Cys FMO3 was inhibited by sulindac in a substrate-dependent manner, presumably because of selective interaction between the variant enzyme and the substrate. The results suggest that the effects of genetic variation of human FMO3 could operate at the functional level for N- and S-oxygenation for typical FMO3 substrates. Genetic polymorphism in the human FMO3 gene might lead to unexpected changes of catalytic efficiency for N- and S-oxygenation of xenobiotics and endogenous materials.

Benzydamine↗
PubMed2006

Synthetic inhibitors of cytochrome P-450 2A6: inhibitory activity, difference spectra, mechanism of inhibition, and protein cocrystallization.

A series of 3-heteroaromatic analogues of nicotine were synthesized to delineate structural and mechanistic requirements for selectively inhibiting human cytochrome P450 (CYP) 2A6. Thiophene, substituted thiophene, furan, substituted furan, acetylene, imidazole, substituted imidazole, thiazole, pyrazole, substituted pyrazole, and aliphatic and isoxazol moieties were used to replace the N-methylpyrrolidine ring of nicotine. A number of potent inhibitors were identified, and several exhibited high selectivity for CYP2A6 relative to CYP2E1, -3A4, -2B6, -2C9, -2C19, and -2D6. The majority of these inhibitors elicited type II difference spectra indicating the formation of a coordinate covalent bond to the heme iron. The majority of inhibitors were reversible inhibitors although several mechanism-based inactivators were identified. Most of the inhibitors were also relatively metabolically stable. X-ray crystal structures of CYP2A6 cocrystallized with three furan analogues bearing methanamino side chains indicated that the amine side chain coordinated to the heme iron. The pyridyl moiety was positioned to accept a hydrogen bond from Asn297, and all three inhibitors exhibited orthogonal aromatic-aromatic interactions with protein side chains. For comparison, the cocrystal structure of 4,4'-dipyridyl disulfide was also obtained and showed that the pyridine moiety could assume a different orientation than that observed for the 3-heteroaromatic pyridines examined. For the 3-heteroromatic pyridines, N-methyl and N,N-dimethyl amino groups increased the apparent Ki and distorted helix I of the protein. Substitution of a phenyl ring for the pyridyl ring also increased the apparent Ki, which is likely to reflect the loss of the hydrogen bonding interaction with Asn297. In contrast, inhibitory potency for other P450s was increased, and the selectivity of the phenyl analogues for CYP2A6 was decreased relative to the pyridyl compounds. The results suggest that inhibitors that compliment the active site features of CYP2A6 can exhibit significant selectivity for CYP2A6 relative to other human liver drug-metabolizing P450s.

Acetylene↗
PubMed2006

Stop codon mutations in the flavin-containing monooxygenase 3 (FMO3) gene responsible for trimethylaminuria in a Japanese population.

The reduced capacity of flavin-containing monooxygenase 3 (FMO3) to N-oxidize trimethylamine (TMA) is believed to cause a metabolic disorder. The aim of this study was to investigate the inter-individual variations of FMO3. Genomic DNA of case subjects that showed only 10-20% of FMO3 metabolic capacity among self-reported trimethylaminuria Japanese volunteers was sequenced. Functional analysis of recombinant FMO3 proteins was also performed. One homozygote for a novel single nucleotide substitution causing a stop codon at Arg500 was observed. The biological parents of this Proband A were heterozygous and showed >90% TMA N-oxygenation metabolic capacity. Another Proband B had the Arg500Stop and Cys197Stop codons. The TMA N-oxygenation metabolic capacities of the father and brother of this Proband B were apparently observed by possessing Arg205Cys mutant that coded for decreased TMA N-oxygenase. Recombinant Arg500Stop FMO3 cDNA expressed in Escherichia coli membranes and a series of highly purified truncation mutants at different positions of the C-terminus of FMO3 showed no detectable functional activity toward typical FMO3 substrates. The results suggest that individuals homozygous for either of the nonsense mutations, Arg500Stop and/or Cys197Stop alleles, in the FMO3 gene can possess abnormal TMA N-oxygenation.

Adolescent↗
PubMed2006

Investigation of structure and function of a catalytically efficient variant of the human flavin-containing monooxygenase form 3.

To characterize the contribution of amino acid 360 to the functional activity of the human flavin-containing monooxygenase form 3 (FMO3) and form 1 (FMO1) in the oxygenation of drugs and chemicals, we expressed four FMO3 variants (i.e., Ala360-FMO3, His360-FMO3, Gln360-FMO3, and Pro360-FMO3) and one FMO1 variant (i.e., Pro360-FMO1) and compared them to wild-type enzymes (Leu360-FMO3 and His360-FMO1, respectively). The amino acid substitutions were introduced into wild-type FMO3 or FMO1 cDNA by site-directed mutagenesis. The thermal stability of variants of Leu360 FMO3 was also studied, and the thermal stability was significantly different from that of wild-type FMO3. The influence of different substrates to modulate the catalytic activity of FMO3 variants was also examined. Selective functional substrate activity was determined with mercaptoimidazole, chlorpromazine, and 10-[(N,N-dimethylaminopentyl)-2-(trifluoromethyl)]phenothiazine. Compared with wild-type FMO3, the Ala360-FMO3 and His360-FMO3 variants were less catalytically efficient for mercaptoimidazole S-oxygenation. N-Oxygenation of chlorpromazine was significantly less catalytically efficient for His360-FMO3 compared with wild-type FMO3. Human Pro360-FMO1 was significantly more catalytically efficient at S-oxygenating mercaptoimidazole and chlorpromazine compared with wild-type FMO1. The data support the mechanism that the Pro360 loci affect thermal stability of FMO3. Because different amino acids at position 360 affect substrate oxygenation in a unique fashion compared with that of FMO3 stimulation, we conclude that the mechanism of stimulation of FMO3 is distinct from that of enzyme catalysis. A molecular model of human FMO3 was also constructed to help explain the results. The increase in catalytic efficiency observed for Pro360 in human FMO3 was also observed when the His of FMO1 was replaced by Pro at loci 360.

Amino Acid Substitution↗
PubMed2006

Human flavin-containing monooxygenases.

This review summarizes recent information concerning the pharmacological and toxicological significance of the human flavin-containing monooxygenase (FMO, EC 1.14.13.8). The human FMO oxygenates nucleophilic heteroatom-containing chemicals and drugs and generally converts them into harmless, polar, readily excreted metabolites. Sometimes, however, FMO bioactivates chemicals into reactive materials that can cause toxicity. Most of the interindividual differences of FMO are due to genetic variability and allelic variation, and splicing variants may contribute to interindividual and interethnic variability observed for FMO-mediated metabolism. In contrast to cytochrome P450 (CYP), FMO is not easily induced nor readily inhibited, and potential adverse drug-drug interactions are minimized for drugs prominently metabolized by FMO. These properties may provide advantages in drug design and discovery, and by incorporating FMO detoxication pathways into drug candidates, more drug-like materials may be forthcoming. Although exhaustive examples are not available, physiological factors can influence FMO function, and this may have implications for the clinical significance of FMO and a role in human disease.

Disease↗
PubMed2005

Quantitative analysis of FMO gene mRNA levels in human tissues.

The developmentally and tissue-specific expression of flavin-containing monooxygenase (FMO) enzymes has been previously characterized in a number of animal species, including humans, mice, rats, and rabbits. In this study, we used sensitive real-time reverse transcription-polymerase chain reaction methodology to systematically quantify the steady-state mRNA levels of FMO1, 2, 3, 4, and 5 in human tissues. We examined the developmental regulation of these enzymes in brain tissue. FMO1 was found to be down-regulated in human adult brain. The amount of other FMO mRNAs in human brains in different age groups was not significantly different. The study also provided a systematic quantitative comparison of the steady-state mRNA levels of FMO1 to 5 in several major human organs (i.e., liver, lung, kidney, small intestine, and brain). The nature of the quantitative analysis allowed a comprehensive comparison of each FMO mRNA in different tissues as well as among FMO isoforms in the same tissue. A comparison between fetal liver and adult liver showed that FMO1 was the only FMO that was down-regulated; all other FMOs had greater amounts of mRNA in adult liver. FMO5 was the most prominent FMO form detected in fetal liver. The FMO5 mRNA level was nearly as abundant as FMO3 in adult liver. Whereas other FMOs displayed a significant, dominant tissue-specific mRNA profile (i.e., FMO1 in kidney, FMO2 in lung, FMO3 and FMO5 in adult liver), FMO4 mRNA was observed more broadly at relatively comparable levels in liver, kidney, lung, and small intestine.

Aging↗
PubMed2005

Some distinctions between flavin-containing and cytochrome P450 monooxygenases.

This minireview summarizes information concerning the differences and similarities of the human flavin-containing- (FMO, E.C. 1.14.13.8) and the cytochrome P450-monooxygenases (CYP, E.C. 1.14.14.1). Human FMO oxygenates soft nucleophiles. CYP mainly catalyzes C-H abstraction but also oxidizes nitrogen- and sulfur-containing compounds. Both FMO and CYP generally convert lipophilic compounds into more hydrophilic metabolites. The mechanism by which each monooxygenase operates is quite distinct. Sometimes, CYP or FMO bioactivate chemicals to reactive metabolites but to date, drug toxicity thus far observed in the clinic is mainly the result of CYP-dependent oxidation. Both FMO and CYP possess genetic variability that may contribute to inter-individual variability observed for drug metabolism. In contrast to CYP, FMO is not induced or readily inhibited and potential adverse drug-drug interactions are minimized for drugs prominently metabolized by FMO. These properties may provide advantages in drug design, and by incorporating FMO detoxication pathways into drug candidates, more drug-like materials may emerge.

Animals↗
PubMed2005

Synthesis and in vitro biological evaluation of a carbon glycoside analogue of morphine-6-glucuronide.

Attachment of a glucose moiety to 6-beta-aminomorphine afforded compound 3, where the glucose moiety was linked to the C-6 nitrogen atom by a two-carbon bridge. The synthesis of 3 was accomplished in eight steps from 3-triisopropylsilyl-6-beta-aminomorphine and 2,3,4,6-tetra-O-benzyl-D-glucose. The C-glycoside 3 was prepared with the objective of examining a metabolically stable analogue of morphine-6-glucuronide and determining the potency and selectivity of opioid receptor binding. Competition binding assays showed that 3 bound to the mu opioid receptor with a Ki value of 3.5 nM. The C-glycoside 3 exhibited delta/mu and kappa/mu selectivity ratios of 76 and 165, respectively. The synthetic intermediate (i.e., benzyl precursor, compound 11) bound to the mu opioid receptor with a Ki value of 0.5 nM, was less selective for the mu opioid receptor. The [35S]GTPgammaS assay was used to evaluate the functional properties of compounds 3 and 11. Compound 3 was determined to be a full agonist at the mu opioid receptor, whereas compound 11 was found to be a partial agonist. Compound 3 was determined to be very stable in the presence of human liver S9, and rat and monkey liver microsomes: no detectable loss of 3 was observed up to 90 min. Compound 3 was also very stable at pH 2 and pH 7.4, suggesting that 3 possessed properties for sustained duration of action.

Animals↗
PubMed2005

5-substituted, 6-substituted, and unsubstituted 3-heteroaromatic pyridine analogues of nicotine as selective inhibitors of cytochrome P-450 2A6.

A series of 5- and 6-substituted and unsubstituted 3-heteroaromatic analogues of nicotine were synthesized in an effort to delineate the structural requirements for selectively inhibiting human cytochrome P-450 (CYP) 2A6, the major nicotine metabolizing enzyme. Thiophene, substituted thiophene, furan, substituted furan, imidazole, substituted imidazole, pyridine, substituted pyridine, thiazole, and quinoline moieties were used to replace the N-methylpyrrolidine ring of nicotine. Bromo and methyl groups were introduced at the 5-position of the pyridine ring and fluoro, chloro, and methoxy groups were placed at the 6-position of the pyridine ring in order to explore the structure-activity relationship (SAR) of inhibition of CYP2A6. The inhibitory activity of the most potent CYP2A6 inhibitors on the functional activity of human cytochrome P450s 3A4, 2E1, 2B6, 2C9, 2C19, and 2D6 was also examined to determine inhibitor selectivity. We identified 36 compounds that were more potent than nicotine at inhibition of coumarin 7-hydroxylase (CYP2A6) activity. We also found a number of compounds to be highly selective for the inhibition of human CYP2A6 versus the other human CYPs examined.

Aryl Hydrocarbon Hydroxylases↗
PubMed2005

Dynamic medicinal chemistry in the elaboration of morphine-6-glucuronide analogs.

This review discusses the role of dynamic medicinal chemistry in the design and development of more effective opioids for the treatment of pain. Human Phase II clinical studies have shown that morphine-6-glucuronide (M6G) has equivalent analgesic effects to morphine and an improved side effect profile particularly at reducing the tendency to cause nausea, vomiting, sedation and respiratory depression. Based on these clinical observations, a new class of pain medication could be developed. Despite the promise, M6G is not an ideal drug because bioavailability is low and hydrolysis occurs in the gut. The literature covered includes a comprehensive list of work that illustrates: (i) the role of drug metabolism and drug disposition concepts in M6G analog drug development, (ii) the use of dynamic medicinal chemistry in improving M6G pharmaceutical properties, and (iii) the role of drug metabolism in enhancing bioavailability of M6G. Using optimized dynamic medicinal chemistry procedures for drug design and development, understanding the use of drug development concepts in early drug development and applying new methods from other fields may help advance this field of drug development. This review summarizes studies that support the feasibility of elaborating longer-acting, less expensive pain medications with possibly a safer profile of side effects. Development of new pain medications for cancer and other diseases based on M6G could provide novel agents that could balance optimal analgesia with a decreased occurrence of adverse side effects.

Analgesics, Opioid↗
PubMed2004

Synthesis and biological evaluation of some 6-arylamidomorphines as analogues of morphine-6-glucuronide.

A series of 6-beta-arylamidomorphines was synthesized and biologically evaluated. Various aryl substituents were introduced into the arylamidomorphines to examine substituent structure-activity relationships. Competition binding assays showed that compounds 10a-h bound to the mu opioid receptor with high affinity (0.2-0.6 nM). Functional assays showed that compounds 10a-h acted as full mu opioid receptor agonists. The ED(50) of compound 10e.HCl as an analgesic was 12.6 mg/kg in the tail flick latency test in the rat.

Animals↗
PubMed2004

Design, chemical synthesis, and biological evaluation of thiosaccharide analogues of morphine- and codeine-6-glucuronide.

A series of 6-beta-thiosaccharide analogues of morphine-6-glucuronide (M6G) and codeine-6-glucuronide (C6G) were synthesized and evaluated with the objective of preparing an analogue of M6G with improved biological activity. The affinity of the thiosaccharide analogues of M6G and C6G was examined by competitive binding assays at mu, delta, and kappa opioid receptors. The thiosaccharide compounds in the morphine series 5b, 5e, 6a, and 6c showed 1.5-2.4-fold higher affinity for the mu receptor than M6G, but were generally less selective than M6G. The functional activity of the M6G and C6G analogues was examined with the [35S]GTP-gamma-S assay. Compounds 5b and 5e were determined to be full mu agonists, whereas compounds 6a and 6c were partial mu agonists. The in vivo antinociceptive activity of compound 5b was evaluated by the tail flick latency test, giving an ED50 of 2.5 mg/kg.

Analgesics, Opioid↗
PubMed2004

The implications of polymorphisms in mammalian flavin-containing monooxygenases in drug discovery and development.

Use of the human flavin-containing monooxygenases (FMOs) in drug design and discovery could represent a paradigm shift in drug development and basic research. Although FMOs have been previously viewed as minor contributors to drug metabolism, the advantages associated with using FMOs to diversify the metabolism of a drug are now being recognized. Because FMOs typically oxygenate a wide variety of nucleophilic compounds to polar, benign metabolites, and because drugs do not induce expression of FMOs or inhibit their activity, potential drug-drug interactions are minimized. Interindividual variation for this class of enzyme is largely dependent on genetic variation. Examples of FMO allelic variation and splicing variants suggest that these genetic mutations could contribute to the interindividual and interethnic variability of FMO-mediated metabolism.

Animals↗
PubMed2004

Effects of the dietary supplements, activated charcoal and copper chlorophyllin, on urinary excretion of trimethylamine in Japanese trimethylaminuria patients.

Trimethylaminuria (TMAU) is a metabolic disorder characterized by the inability to oxidize and convert dietary-derived trimethylamine (TMA) to trimethylamine N-oxide (TMAO). This disorder has been relatively well-documented in European and North American populations, but no reports have appeared regarding patients in Japan. We identified seven Japanese individuals that showed a low metabolic capacity to convert TMA to its odorless metabolite, TMAO. The metabolic capacity, as defined by the concentration of TMAO excreted in the urine divided by TMA concentration plus TMAO concentration, in these seven individuals ranged from 70 to 90%. In contrast, there were no healthy controls examined with less than 95% of the metabolic capacity to convert TMA to TMAO. The intake of dietary charcoal (total 1.5 g charcoal per day for 10 days) reduced the urinary free TMA concentration and increased the concentration of TMAO to normal values during charcoal administration. Copper chlorophyllin (total 180 mg per day for 3 weeks) was also effective at reducing free urinary TMA concentration and increasing TMAO to those of concentrations present in normal individuals. In the TMAU subjects examined, the effects of copper chlorophyllin appeared to last longer (i.e., several weeks) than those observed for activated charcoal. The results suggest that the daily intake of charcoal and/or copper chlorophyllin may be of significant use in improving the quality of life of individuals suffering from TMAU.

Adult↗
PubMed2004

Nicotine-related alkaloids and metabolites as inhibitors of human cytochrome P-450 2A6.

S-(-)-Nicotine and 13 of the most prevalent nicotine-related alkaloids and metabolites (i.e., S-(-)-nornicotine, myosmine, beta-nicotyrine, S-cotinine, S-norcotinine, S-(-)-nicotine N-1'-oxide, S-(-)-nicotine Delta1'-5'-iminium ion, S-(-)-anabasine, S-(-)-N-methylanabasine, anabaseine, S-(-)-anatabine, nicotelline, and 2,3'-bipyridyl) were evaluated as inhibitors of human cDNA-expressed cytochrome P-450 2A6 (CYP2A6) mediated coumarin 7-hydroxylation. Tobacco alkaloids myosmine, S-(-)-nornicotine, S-cotinine, S-norcotinine, S-(-)-nicotine N-1'-oxide, S-(-)-nicotine Delta1'-5'-iminium ion, S-(-)-N-methylanabasine, anabaseine, and nicotelline had Ki values for inhibition of coumarin 7-hydroxylation ranging from 20 microM to more than 300 microM whereas nicotine and S-(-)-anatabine were much more potent (i.e. 4.4 and 3.8 microM, respectively). The tobacco alkaloids 2,3'-bipyridyl (7.7 microM) and S-(-)-anabasine (5.4 microM), were somewhat less potent compared with S-(-)-nicotine or S-(-)-anatabine in inhibition of human CYP2A6. beta-Nicotyrine, in which the N-methylpyrrolidino moiety of nicotine was replaced by the aromatic N-methylpyrrole ring, was shown to inhibit human CYP2A6 with much greater potency (Ki=0.37 microM) compared with S-(-)-nicotine. Among the compounds examined, only nicotine and beta-nicotyrine were mechanism-based inhibitors of human CYP2A6. The potency of the mechanism-based CYP2A6 inhibitors suggests that, for smokers, modulation of CYP2A6 may be greater than that predicted on the basis of serum concentration of these alkaloids. Our results indicate that the prominent nicotine-related alkaloid beta-nicotyrine present after smoking potently inhibits human CYP2A6.

Alkaloids↗
PubMed2004

Effect of total parenteral nutrition and choline on hepatic flavin-containing and cytochrome P-450 monooxygenase activity in rats.

Total parenteral nutrition provides nutrition by infusion into the systemic circulation. Bypassing the intestine and processes associated with absorption can cause additional pathophysiological changes to occur. For example, in rats, normal gut and pancreatic cell function may change, absorptive capacity may be altered, and enzyme functional activity including drug metabolism may be affected. The objective of this study was to examine the effects of a control diet or a diet of total parenteral nutrition in the presence or absence of choline on urinary biomarkers and hepatic microsome functional activity from rats. Selective functional markers of cytochrome P-4502E1 (CYP2E1) and flavin-containing monooxygenase (FMO) were examined in vitro. The N-oxygenation of trimethylamine was used as an in vivo selective functional marker for FMO. After the administration of total parenteral nutrition plus choline for 5 days, the urinary excretion of trimethylamine and trimethylamine N-oxide declined approximately 7- and 3-fold, respectively, compared with rats treated with control diet. The concentration of urinary biogenic amines was also significantly affected by total parenteral nutrition. Compared with control animals, rats administered total parenteral nutrition plus choline for 5 days showed a decrease of approximately 5- and 2-fold in urinary dopamine and norepinephrine concentration, respectively. To examine a molecular basis for the influence of total parenteral nutrition +/- choline on monooxygenase regulation, hepatic microsomal activity of the FMO and CYP2E1 was examined. Compared with animals treated with a control diet, total parenteral nutrition plus choline in rats caused a 3-fold increase in hepatic microsomal FMO and a 2-fold increase in hepatic cytochrome CYP2E1 functional activity, respectively. Although the data did not reach statistical significance, selective immunoblot studies using hepatic microsomes from rats treated with total parenteral nutrition + choline showed that compared with controls, FMO1 protein was decreased 1.4-fold and FMO3 increased 1.3-fold, respectively. In hepatic microsomes from rats treated with total parenteral nutrition + choline, compared with control animals, FMO4 immunoreactivity was increased 1.6-fold. The data suggest that total parenteral nutrition has a detectable effect on modulating rat FMO3, FMO4, and CYP2E1 monooxygenase functional activity. The clinical relevance of these results is unknown but may be of significance for individuals receiving total parenteral nutrition and those afflicted with trimethylaminuria.

Animals↗
PubMed2004

Alternative processing events in human FMO genes.

In humans, flavin-containing monooxygenase (FMO) functional diversity is determined by the expression of five FMO genes, named FMO1 to FMO5, and their variants. In this study, we systematically analyzed transcripts of FMO1 to FMO5 in different human tissues by reverse-transcription-polymerase chain reaction and identified a large number of splice variants. Exon skipping was the major splicing event observed. Normally spliced transcripts were generally the prominent transcript detected. For FMO1, FMO2, and FMO3, two to three different splice variants were identified, and their corresponding expression was always low in the tissues examined. For FMO5 and particularly for FMO4, more complex alternative splice patterns were observed, with five and seven splice variants detected, respectively. Most identified FMO splice variants either caused a frame-shift or lacked essential functional sites. The corresponding transcripts were therefore incapable of encoding a functional enzyme and were not analyzed further in this study. However, a common in-frame exon 3- (exon 4 for FMO4) deleted variant, leading to the deletion of 63 amino acids, was identified for FMO1, FMO3, FMO4, and FMO5. To examine the functional importance of exon 3-deletion, FMO1, FMO3, FMO4 and the corresponding exon-deleted proteins were expressed as fusion proteins. Activity studies were done with two selective functional FMO substrates, methimazole, and 10-(N,N-dimethylaminopentyl)-2-(trifluoromethyl)phenothiazine and exon 3- (exon 4 for FMO4) deleted FMOs were not able to catalyze the S- and N-oxygenation of these substrates, respectively. It is not clear whether these FMO splice variants can oxygenate other substrates, including those that remain to be discovered.

Alternative Splicing↗