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Ronald N Hines

Publications and source records attributed to Ronald N Hines.

At least 19 recordsLinked to original sources
PubMed2006

Identification and functional analysis of common human flavin-containing monooxygenase 3 genetic variants.

Flavin-containing monooxygenases (FMOs) are important for the disposition of many therapeutics, environmental toxicants, and nutrients. FMO3, the major adult hepatic FMO enzyme, exhibits significant interindividual variation. Eighteen FMO3 single-nucleotide polymorphism (SNP) frequencies were determined in 202 Hispanics (Mexican descent), 201 African Americans, and 200 non-Latino whites. Using expressed recombinant enzyme with methimazole, trimethylamine, sulindac, and ethylenethiourea, the novel structural variants FMO3 E24D and K416N were shown to cause modest changes in catalytic efficiency, whereas a third novel variant, FMO3 N61K, was essentially devoid of activity. The latter variant was present at an allelic frequency of 5.2% in non-Latino whites and 3.5% in African Americans, but it was absent in Hispanics. Inferring haplotypes using PHASE, version 2.1, the greatest haplotype diversity was observed in African Americans followed by non-Latino whites and Hispanics. Haplotype 2A and 2B, consisting of a hypermorphic promoter SNP cluster (-2650C>G, -2543T>A, and -2177G>C) in linkage with synonymous structural variants was inferred at a frequency of 27% in the Hispanic population, but only 5% in non-Latino whites and African Americans. This same promoter SNP cluster in linkage with one or more hypomorphic structural variant also was inferred in multiple haplotypes at a total frequency of 5.6% in the African-American study group but less than 1% in the other two groups. The sum frequencies of the hypomorphic haplotypes H3 [15,167G>A (E158K)], H5B [-2650C>G, 15,167G>A (E158K), 21,375C>T (N285N), 21,443A>G (E308G)], and H6 [15,167G>A (E158K), 21,375C>T (N285N)] was 28% in Hispanics, 23% in non-Latino whites, and 24% in African Americans.

Black or African American↗
PubMed2006

Epirubicin glucuronidation and UGT2B7 developmental expression.

The usefulness of epirubicin in the treatment of adult and childhood malignant diseases is related in part to the potential reduction in cardiac toxicity compared with that of other anthracyclines given at equivalent doses. An important pathway for epirubicin detoxification is UGT2B7-dependent glucuronidation. This study was implemented to provide a preclinical evaluation of the metabolism of epirubicin with respect to age-related changes in epirubicin glucuronidation in pediatric liver microsomes. Rates of epirubicin glucuronidation and levels of UGT2B7 were determined for liver microsomes from four pediatric age categories (n = 32) and one adult age category (n = 8). Both sets of data showed an increase in UGT2B7 activity and content with increasing age. Epirubicin glucuronidation activity in the adult group was statistically higher compared with all pediatric age groups (p < or = 0.01). UGT2B7 expression also was statistically higher in adults compared with children below 11 years of age, with evidence of significant differences in protein levels among the pediatric age categories. A positive correlation (r = 0.68) between UGT2B7 levels and postnatal age was observed, suggesting a progressive increase in UGT2B7 protein expression with increasing age. However, allometric scaling using the (3/4) power rule suggested no difference in activity between any of the pediatric age categories and the adult, although only a single neonatal sample was included in the analysis. In summary, these in vitro data show differences in epirubicin glucuronidation and UGT2B7 content within pediatric age groups and support the use of epirubicin in pediatric patients at least 6 months of age.

Adolescent↗
PubMed2006

Enzyme-mediated protein haptenation of dapsone and sulfamethoxazole in human keratinocytes: I. Expression and role of cytochromes P450.

Cutaneous drug reactions (CDRs) are among the most common adverse drug reactions and are responsible for numerous minor to life-threatening complications. Several arylamine drugs, such as sulfamethoxazole (SMX) and dapsone (DDS), undergo bioactivation, resulting in adduction to cellular proteins. These adducted proteins may initiate the immune response that ultimately results in a CDR. Recent studies have demonstrated that normal human epidermal keratinocytes (NHEKs) can bioactivate these drugs, resulting in protein haptenation. We sought to identify the enzyme(s) responsible for this bioactivation in NHEKs. Using immunofluorescence confocal microscopy and an adduct-specific enzyme-linked immunosorbent assay (ELISA), we found that N-acetylation of the primary amine of SMX and DDS markedly reduced the level of protein haptenation in NHEKs. Detection of mRNA and/or protein confirmed the presence of CYP3A4, CYP3A5, and CYP2E1 in NHEKs. In contrast, although a faint band suggestive of CYP2C9 protein was detected in one NHEK sample, a CYP2C9 message was not detectable. We also examined the ability of chemical inhibitors of cytochromes P450 (aminobenzotriazole and 1-dichloroethylene) and cyclooxygenase (indomethacin) to reduce protein haptenation when NHEKs were incubated with SMX or DDS by either confocal microscopy or ELISA. These inhibitors did not significantly attenuate protein adduction with either SMX or DDS, indicating that cytochromes P450 and cyclooxygenase do not play important roles in the bioactivation of these xenobiotics in NHEKs and thus suggesting the importance of other enzymes in these cells.

Acetylation↗
PubMed2006

Enzyme-mediated protein haptenation of dapsone and sulfamethoxazole in human keratinocytes: II. Expression and role of flavin-containing monooxygenases and peroxidases.

Arylamine compounds, such as sulfamethoxazole (SMX) and dapsone (DDS), are metabolized in epidermal keratinocytes to arylhydroxylamine metabolites that auto-oxidize to arylnitroso derivatives, which in turn bind to cellular proteins and can act as antigens/immunogens. Previous studies have demonstrated that neither cytochromes P450 nor cyclooxygenases mediate this bioactivation in normal human epidermal keratinocytes (NHEKs). In this investigation, we demonstrated that methimazole (MMZ), a prototypical substrate of the flavin-containing monooxygenases (FMOs), attenuated the protein haptenation observed in NHEKs exposed to SMX or DDS. In addition, recombinant FMO1 and FMO3 were able to bioactivate both SMX and DDS, resulting in covalent adduct formation. Western blot analysis confirmed the presence of FMO3 in NHEKs, whereas FMO1 was not detectable. In addition to MMZ, 4-aminobenzoic acid hydrazide (ABH) also attenuated SMX- and DDS-dependent protein haptenation in NHEKs. ABH did not alter the bioactivation of these drugs by recombinant FMO3, suggesting its inhibitory effect in NHEKs was due to its known ability to inhibit peroxidases. Studies confirmed the presence of peroxidase activity in NHEKs; however, immunoblot analysis and reverse transcription-polymerase chain reaction indicated that myeloperoxidase, lactoperoxidase, and thyroid peroxidase were absent. Thus, our results suggest an important role for FMO3 and yet-to-be identified peroxidases in the bioactivation of sulfonamides in NHEKs.

Cells, Cultured↗
PubMed2006

Population-based analysis of methadone distribution and metabolism using an age-dependent physiologically based pharmacokinetic model.

Limited pharmacokinetic (PK) and pharmacodynamic (PD) data are available to use in methadone dosing recommendations in pediatric patients for either opioid abstinence or analgesia. Considering the extreme inter-individual variability of absorption and metabolism of methadone, population-based PK would be useful to provide insight into the relationship between dose, blood concentrations, and clinical effects of methadone. To address this need, an age-dependent physiologically based pharmacokinetic (PBPK) model has been constructed to systematically study methadone metabolism and PK. The model will facilitate the design of cost-effective studies that will evaluate methadone PK and PD relationships, and may be useful to guide methadone dosing in children. The PBPK model, which includes whole-body multi-organ distribution, plasma protein binding, metabolism, and clearance, is parameterized based on a database of pediatric PK parameters and data collected from clinical experiments. The model is further tailored and verified based on PK data from individual adults, then scaled appropriately to apply to children aged 0-24 months. Based on measured variability in CYP3A enzyme expression levels and plasma orosomucoid (ORM2) concentrations, a Monte-Carlo-based simulation of methadone kinetics in a pediatric population was performed. The simulation predicts extreme variability in plasma concentrations and clearance kinetics for methadone in the pediatric population, based on standard dosing protocols. In addition, it is shown that when doses are designed for individuals based on prior protein expression information, inter-individual variability in methadone kinetics may be greatly reduced.

Adult↗
PubMed2006

Pharmacogenomics and the future of drug therapy.

With the completion of the human genome project, many investigators are striving to translate the resulting wealth of new information into new and improved clinical practices. Pharmacogenomics represents one of the most promising of these applications for adult- and pediatric-based therapies. This article provides a historical perspective, but most importantly, uses this background to illustrate important principles of the field. The application of pharmacogenomics to asthma therapy is presented as an example of the current status of pharmacogenomics as it is being applied to an important pediatric health problem. Finally, a discussion of future promises and challenges to the application of pharmacogenomics is presented, including economic and ethical issues.

Adrenal Cortex Hormones↗
PubMed2006

The role of flavin-containing monooxygenase (FMO) in the metabolism of tamoxifen and other tertiary amines.

Tamoxifen is utilized in breast cancer therapy and in chemoprevention. Tamoxifen may enhance risk for other neoplasias, especially endometrial cancer. The risk:benefit depends on the rate of metabolic activation versus detoxication. Cytochrome P450-dependent alpha-hydroxylation, followed by sulfonation, represents a metabolic activation pathway, producing products capable of covalent DNA adduction. In contrast, tamoxifen N-oxygenation represents a detoxication pathway, with the caveat that N-oxides can be reduced back to the parent amines. The N-oxygenation pathway will be the focus for this review. Dr. David Kupfer pioneered studies on cytochrome P450 and flavin-containing monooxygenase (FMO) tamoxifen metabolism. We collaborated with Dr. Kupfer's laboratory and recently determined that the low level of tamoxifen N-oxide production in human liver microsomes may be explained by the kinetics of FMO1 versus FMO3.

Amines↗
PubMed2006

A tiered approach to life stages testing for agricultural chemical safety assessment.

A proposal has been developed by the Agricultural Chemical Safety Assessment (ACSA) Technical Committee of the ILSI Health and Environmental Sciences Institute (HESI) for an improved approach to assessing the safety of crop protection chemicals. The goal is to ensure that studies are scientifically appropriate and necessary without being redundant, and that tests emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. The ACSA Life Stages Task Force proposes a tiered approach to toxicity testing that assesses a compound's potential to cause adverse effects on reproduction, and that assesses the nature and severity of effects during development and adolescence, with consideration of the sensitivity of the elderly. While incorporating many features from current guideline studies, the proposed approach includes a novel rat reproduction and developmental study with enhanced endpoints and a rabbit development study. All available data, including toxicokinetics, ADME data, and systemic toxicity information, are considered in the design and interpretation of studies. Compared to existing testing strategies, the proposed approach uses fewer animals, provides information on the young animal, and includes an estimation of human exposure potential for making decisions about the extent of testing required.

Agrochemicals↗
PubMed2006

Developmental and tissue-specific expression of human flavin-containing monooxygenases 1 and 3.

Substantial changes occur in drug and toxicant disposition during early life stages that can impact therapeutic efficacy and adverse reactions to drugs and toxicants. Of the many parameters involved, alterations in drug metabolism are of major importance. Although the cytochrome P450-dependent monooxygenases are accepted as playing a substantial role in drug and toxicant metabolism, the flavin-containing monooxygenases (FMOs) also have an important role. Apparently unique to the human, FMO3 is the most abundant FMO family member in the adult human liver, whereas FMO1 dominates in most animal models. However, early studies documented that FMO1 is the most abundant FMO enzyme in the human fetal liver, whereas FMO3 is essentially absent. This review focuses on recent studies characterising human FMO ontogeny and, in particular, the 'switch' in hepatic FMO enzyme expression. Because it is so closely related, tissue-specific expression patterns also are examined. Finally, a summary of what is known in animal models is presented as a point of comparison.

Animals↗
PubMed2005

Developmental expression of aryl, estrogen, and hydroxysteroid sulfotransferases in pre- and postnatal human liver.

Aryl- (SULT1A1), estrogen- (SULT1E1), and hydroxysteroid- (SULT2A1) sulfotransferases (SULTs) are active determinants of xenobiotic detoxication and hormone metabolism in the adult human liver. To investigate the role of these conjugating enzymes in the developing human liver, the ontogeny of immunoreactive SULT1A1, SULT1E1, and SULT2A1 expression was characterized in a series of 235 pre- and postnatal human liver cytosols ranging in age from early gestation to a postnatal age of 18 years. Interindividual variability in expression levels was apparent for all three SULTs in pre- and postnatal liver samples. Expression of the three SULTs displayed distinctly different developmental profiles. Semiquantitative Western blot analyses indicated that SULT1A1 and SULT2A1 immunoreactive protein levels were readily detectable in the majority of developmental human liver cytosols throughout the prenatal period. Whereas SULT1A1 expression did not differ significantly among the various developmental stages, SULT2A1 expression increased during the third trimester of gestation and continued to increase during postnatal life. By contrast, SULT1E1, a cardinal estrogen-inactivating enzyme, achieved the highest levels of expression during the earliest periods of gestation in prenatal male livers, indicating a requisite role for estrogen inactivation in the developing male. The present analysis suggests that divergent regulatory mechanisms are responsible for the differential patterns of hepatic SULT1A1, SULT1E1, and SULT2A1 immunoreactive protein levels that occur during pre- and postnatal human development, and implicates a major role for sulfotransferase expression in the developing fetus.

Age Factors↗
PubMed2005

Molecular mechanisms regulating human CYP4B1 lung-selective expression.

Lung-selective cytochrome P450 expression is well recognized; however, little is known regarding regulatory mechanisms. To address this knowledge gap, transient expression of CYP4B1/luciferase constructs was used to identify a proximal, positively acting regulatory element, position -139 to -45, that functioned in all cells examined; a negatively acting element, position -457 to -216, that only functioned in HepG2 hepatoblastoma cells; and a distal, positively acting element, position -1087 to -1008, that functioned in A549 or BEAS-2B lung-derived cells but not HepG2 cells or 293 kidney-derived cells. Competitive electrophoretic mobility shift assays further localized specific A549, but not HepG2, nuclear protein binding to two sites within the distal element, CYP4B1 position -1052 to -1042 and -1026 to -1008. Several potential lung-selective transcription factor recognition sequences were identified within these elements. However, attempts to identify specific factor(s) were unsuccessful. In contrast, in vitro DNA/protein binding assays combined with transient expression and mutagenesis studies identified two functional Sephadex protein/Krüppel-like factor families of transcription factor sites within the proximal element (position -118 to -114 and position -77 to -73) that bound both Sephadex protein 1 (Sp1) and Sephadex protein 3 (Sp3) in vitro. Furthermore, Sp1-dependent synergistic regulation was observed in A549 cells involving the proximal and distal regulatory elements. Chromatin immunoprecipitation assays demonstrated binding of neither Sp1 nor Sp3 to the CYP4B1 proximal element in human liver tissue, whereas selective Sp1 binding was observed in human lung tissue. Thus, the composite findings are consistent with both the proximal Sp1 elements and the distal regulatory element acting to synergistically control CYP4B1 lung-selective expression.

Aryl Hydrocarbon Hydroxylases↗
PubMed2005

Sp1 and Sp3 regulate basal transcription of the human CYP2F1 gene.

Selective transcription of the human CYP2F1 gene in lung tissues may control the susceptibilities of this organ to diverse pneumotoxicants and lung carcinogens. However, the mechanisms responsible for CYP2F1 organ-selective transcription have not been elucidated. The objectives of the current studies were to identify and characterize basal transcription elements within the TATA-less promoter region of CYP2F1. Four putative Sp1-like sites were identified in the CYP2F1 promoter. Competitive electrophoretic mobility shift assay analysis with mutated oligonucleotide probes and lung A549 cell nuclear extract, along with supershift studies using antibodies to either Sp1 or Sp3 proteins, demonstrated that all four sites formed three specific protein-DNA complexes. Mutations in any of the four core Sp1-like motifs abolished protein-DNA binding. Western blot analysis of both human tissues and cells showed that Sp1 was considerably higher in lung than liver and that Sp3 was much higher in liver than lung. Promoter activation of a luciferase reporter construct was sequentially increased by addition of each of the four Sp1-like motifs in lung A549 cells but not in liver HepG2 cells. Cotransfection of a Sp1 expression vector with the reporter construct dramatically increased luciferase activity in either A549 cells or Sp1-deficient Drosophila Schneider line 2 (SL-2) cells. However, similar cotransfections with an Sp3 expression vector failed to increase activity. Cotransfection of both the Sp1 and Sp3 expression vectors considerably decreased Sp1-mediated activity in A549 cells and abolished activity in SL-2 cells. Thus, these studies demonstrated that four Sp1-dependent proximal promoter elements drive organ-selective CYP2F1 gene transcription, and that Sp1 and Sp3 factors interact to modulate constitutive CYP2F1 transcription in lung cells.

Base Sequence↗
PubMed2005

Discovery of novel flavin-containing monooxygenase 3 (FMO3) single nucleotide polymorphisms and functional analysis of upstream haplotype variants.

The flavin-containing monooxygenases (FMOs) are important for xenobiotic metabolism. FMO3, the predominant FMO enzyme in human adult liver, exhibits significant interindividual variation that is poorly understood. This study was designed to identify common FMO3 genetic variants and determine their potential for contributing to interindividual differences in FMO3 expression. FMO3 single nucleotide polymorphism (SNP) discovery was accomplished by resequencing DNA samples from the Coriell Polymorphism Discovery Resource. Population-specific SNP frequencies were determined by multiplexed, single-base extension using DNA from 201 Hispanic American (Mexican descent), 201 African American, and 200 White (northern European descent) subjects. Haplotypes were inferred and population frequencies estimated using PHASE version 2.1. Multiple site-directed mutagenesis was used to introduce inferred upstream haplotypes into an FMO3/luciferase construct for functional analysis in HepG2 cells. Sequence analysis revealed seven FMO3 upstream SNPs, 11 exon SNPs, and 22 intron SNPs. Five of the latter fell within consensus splice sites. A g.72G>T variant (E24D) is predicted to impact the structure of the Rossmann fold involved in FAD binding, whereas a g.11177C>A variant (N61K) is predicted to disrupt the secondary structure of a conserved membrane interaction domain. Seven common (>1%) promoter region haplotypes were inferred in one or more of the study populations that differed in estimated frequency among the groups. Haplotype 2 resulted in an 8-fold increase in promoter activity, whereas haplotypes 8 and 15 exhibited a near complete loss of activity. In conclusion, FMO3 promoter haplotype variants modulate gene function and probably contribute to interindividual differences in FMO3 expression.

Amino Acid Sequence↗
PubMed2005

Haplotype and functional analysis of four flavin-containing monooxygenase isoform 2 (FMO2) polymorphisms in Hispanics.

OBJECTIVES: Previous work defined two flavin-containing monooxygenase 2 (FMO2) alleles. The major allele, FMO2*2 (g.23,238C>T), encodes truncated inactive protein (p.X472) whereas the minor allele, FMO2*1, present in African- and Hispanic-American populations, encodes active protein (p.Q472). Recently, four common (27 to 51% incidence) FMO2 single nucleotide polymorphisms (SNPs) were detected in African-Americans (N=50); they encode the following protein variants: p.71Ddup, p.V113fs, p.S195L and p.N413 K. Our objectives were to: (1) determine the incidence of these SNPs in 29 Hispanic individuals previously genotyped as g.23,238C (p.Q472) and 124 previously genotyped as homozygous g.23,238 T (p.X472); (2) determine FMO2 haplotypes in this population; and (3) assess the functional impact of SNPs in expressed proteins. METHODS: SNPs were detected via allele-specific oligonucleotide amplification coupled with real-time or electrophoretic product detection, or single strand conformation polymorphism. RESULTS: The g.7,700_7,702dupGAC SNP (p.71Ddup) was absent. The remaining SNPs were present but, except for g.13,732C>T (p.S195L), were less common in the current Hispanic study population versus the previously described African-Americans. Only expressed p.N413 K was as active as p.Q472, as determined by methimazole- and ethylenethiourea-dependent oxidation. Haplotype determination demonstrated that the g.10,951delG (p.V113fs), g.13,732C>T (p.S195L) and g.22,060T>G (p.N413 K) variants segregated with g.23,238C>T (p.X472). CONCLUSIONS: SNPs would not alter FMO2 activity in individuals possessing at least one FMO2*1 allele. It is likely that these SNPs will segregate similarly in African-American populations. Therefore, estimates that 26% of African-Americans and 2-7% of Hispanic-Americans have at least one FMO2*1 allele should closely reflect the percentages producing active FMO2 protein.

Alleles↗
PubMed2005

Flavin-containing monooxygenase genetic polymorphism: impact on chemical metabolism and drug development.

The flavin-containing monooxygenases (FMOs) metabolize a broad range of therapeutics. Consisting of five gene products in humans (FMO1-5), the different FMO family members exhibit pronounced tissue- and temporal-specific expression patterns. Substantial interindividual differences are also observed, and the inability to modulate with exogenous agents is consistent with an important role for genetic variation. Several rare FMO3 alleles causative for trimethylaminuria have been well characterized. However, the identification and characterization of functional FMO1-5 polymorphisms has been more recent. Although none of these polymorphisms has been associated with an adverse drug reaction, the continued broadening of our therapeutic armamentarium makes such an event likely in the future. Furthermore, at least one example has been reported for a direct association between FMO3 polymorphism and therapeutic efficacy. Thus, it is anticipated that knowledge regarding functionally-relevant FMO genetic variability will become increasingly important for making drug development and patient therapeutic choices.

Drug Design↗
PubMed2004

Two distinct classes of CCAAT box elements that bind nuclear factor-Y/alpha-actinin-4: potential role in human CYP1A1 regulation.

A negative regulatory element (NRE1; position -794 to -774) was previously identified that mediates the downregulation of CYP1A1, including partial suppression of Ah receptor-dependent induction. The CCAAT-box binding protein, nuclear factor-Y (NF-Y), is a component of one of two protein complexes that specifically and competitively bind the CYP1A1 NRE1 in vitro with nearly equal affinity. The second complex involves an unidentified protein(s) called the negative regulatory factor (NRF). Competitive electrophoretic mobility shift assays (EMSA) revealed two distinct classes of NF-Y-binding CCAAT-box elements distinguished by their ability or inability to also bind NRF. To further explore the identity of NRE1-binding proteins, a purification scheme was developed culminating in NRE1-dependent DNA affinity chromatography and sequence analysis. An approximate 106-kDa protein was purified and shown to be alpha-actinin-4 (ACTN4), one of two ubiquitously expressed non-muscle actinins. Electrophoretic mobility shift assays combined with Western blot analysis and co-immunoprecipitation experiments suggested that ACTN4 is associated with the NF-Y complex, but not NRF. Attempts to demonstrate a role for NF-Y/ACTN4 in regulating CYP1A1 expression were unsuccessful, likely due to an inability to significantly change nuclear ACTN4 levels with phosphatidylinositol 3'-kinase agonists and antagonists. However, given ACTN4's known functions and the suspected functions of actin and actin-related proteins in chromatin remodeling and other nuclear events, ACTN4 may assist NF-Y in recruiting chromatin-remodeling complexes or may direct NF-Y/ACTN4-targeted genes to the nuclear matrix and active transcriptional complexes.

Actinin↗
PubMed2004

Differences in FMO2*1 allelic frequency between Hispanics of Puerto Rican and Mexican descent.

A polymorphism for the phase I drug-metabolizing enzyme, flavin-containing monooxygenase isoform 2 (FMO2), encoding either truncated inactive protein, FMO2X472 (FMO2.2A), or full-length active enzyme, FMO2Q472 (FMO2.1), is known and exhibits significant interethnic differences in allelic frequency. FMO2 is the major or sole FMO isoform expressed in the lung of most mammals, including nonhuman primates. To date, FMO2.1 has been found only in African-American and Hispanic populations, rendering individuals with this allele subject to drug metabolism that is potentially different from that of the general population. Approximately 26% of African-Americans (n = 180) possess the FMO2*1 allele. In preliminary studies, we initially estimated that 5% of Hispanics (n = 40) have the FMO2*1 allele, but access to large cohorts of individuals of defined national origin has allowed us to determine the occurrence among Mexican-American and Puerto Rican-American groups. We used allele-specific genotyping to detect FMO2*1 from 632 Hispanic individuals, including 280 individuals of Mexican origin and 327 individuals of Puerto Rican origin. Statistical analysis indicated that results from Mexican (five sample sources) and Puerto Rican (three sample sources) samples were consistent with the hypothesis of homogeneity within each group from different sources. Data were subsequently pooled across sources to test for evidence of a difference in occurrence of FMO2*1 between ethnic groups. There was strong evidence (p = 0.0066) that FMO2*1 is more common among Puerto Ricans (7%) than among individuals of Mexican descent (2%). The overall occurrence of FMO2*1 among Hispanics of all origins is estimated to be between 2 and 7%.

Alleles↗