Sulfamethazine Acetylation Research Articles

Effect of acetaminophen on sulfamethazine acetylation in male volunteers.

The effect of acetaminophen on sulfamethazine N-acetylation by human N-acetyltrasferase-2 (NAT2) was studied in 19 (n=19) healthy male volunteers in two different phases. In the first phase of the study the volunteers were given an oral dose of sulfamethazine 500 mg alone and blood and urine samples were collected. After the 10-day washout period the same selected volunteers were again administered sulfamethazine 500 mg along with 1000 mg acetaminophen. The acetylation of sulfamethazine by human NAT2 in both phases with and without acetaminophen was determined by HPLC to establish their respective phenotypes. In conclusion obtained statistics of present study revealed that acetaminophen significantly (P<0.0001) decreased sulfamethazine acetylation in plasma of both slow and fast acetylator male volunteers. A highly significant (P<0.0001) decrease in plasma-free and total sulfamethazine concentration was also observed when acetaminophen was co-administered. Urine acetylation status in both phases of the study was found not to be in complete concordance with that of plasma. Acetaminophen significantly (P<0.0001) increased the acetyl, free and total sulfamethazine concentration in urine of both slow and fast acetylators. Urine acetylation analysis has not been found to be a suitable approach for phenotypic studies.

In Vitro Acetylation of Seven Anti‐glaucoma Agents in Rat, Rabbit and Human Ocular and Liver S9 Fractions

Ocular N‐acetyltransferase(NAT) research has been limited to probe substrate activity in specific tissues from rat or rabbit, but not for a model that represents the whole eye. The comparison of acetylation as a biotransformation pathway between preclinical species and human has not been well documented. We aimed to understand functional ocular NAT activity across rat, rabbit, and human ocular S9 fractions in comparison with liver S9 fractions for seven clinically approved anti‐glaucoma compounds. Specific probe substrates were examined in human ocular, liver, and kidney S9 fractions to asses human NAT1 and 2 activities. High resolution mass spectrometry was utilized to characterize the acetyl conjugate(s) for each anti‐glaucoma agent in ocular and liver S9 fractions. Direct acetyl conjugates were detected across all species in ocular and liver fractions for betaxolol, carteolol and levobunolol, indicating that these compounds are non‐specific NAT substrates. Oxidation and O‐acetylation of levobunolol was detected in rat and rabbit liver S9 only. Species‐ and organ‐specific metabolic differences were observed for metoprolol, metipranolol, propranolol, and timolol. Neither ocular nor liver fractions from rat or rabbit were useful to predict human ocular acetylation in vitro. Ocular and renal S9 fractions did not catalyze the acetylation of sulfamethazine, a NAT2 probe substrate, contrary to the observation in liver S9. The data suggests a strong role of NAT1 in human ocular S9 fractions. This is the first report of direct acetyl conjugates for the b‐adrenergic receptor antagonist class of anti‐glaucoma agents in rat, rabbit and human ocular S9s.

Home spirometry and asthma severity in children

The usefulness of peak expiratory flow monitoring is disputed because of the unreliability of written peak flow diaries. The aim of the present study was to examine the relationship of peak flow and forced expiratory volume in one second (FEV1) variation to other estimates of asthma severity in children, using an electronic home spirometer with automatic data storage. Over a 3-month period, 36 children with mild-to-moderate persistent asthma recorded peak flow and FEV1 electronically twice daily and noted an asthma severity score in a written diary. Bronchial responsiveness was assessed at the beginning and bronchodilator response and asthma-specific quality of life at the end of the study. Variations in peak flow correlated significantly but weakly to bronchial responsiveness and bronchodilator response, but not to the asthma severity score or quality-of-life scores. Within-individual correlations between asthma severity scores and home spirometry indices and between peak flow and FEV1 were highly variable. In conclusion, variations in peak flow and forced expiratory volume in one second, obtained by home spirometry, show poor concordance with other indices of disease activity and with each other. This limits the usefulness of home spirometry in childhood asthma.

Interaction of ibuprofen and probenecid with drug metabolizing enzyme phenotyping procedures using caffeine as the probe drug.

To examine the suspected inhibitory potential of the over-the-counter (OTC) drug ibuprofen on N-acetyltransferase 2 (NAT2) in vitro and in vivo and the possible implications for phenotyping procedures using caffeine as probe drug. We first studied the inhibitory effect of ibuprofen on NAT2 in vitro, using human liver cytosol and sulfamethazine as substrate. In vivo 15 fast and 15 slow acetylating healthy volunteers were treated with a single dose of ibuprofen (800 mg) orally and phenotyped for NAT2, CYP1A2, and xanthine oxidase (XO) with caffeine as probe drug before and during drug treatment. Because of unexpected in vivo results with ibuprofen this study was repeated in 20 healthy volunteers with probenecid, a model substrate of renal organic anion transport (OAT). For phenotyping tests a urine sample was collected 6 h after caffeine (200 mg) intake. The caffeine metabolites acetyl-6-formylamino-3-methyluracil (AFMU), 1-methylxanthine (1MX), 1-methyluric acid (1MU), and 1,7-dimethyluric acid (17MU) were quantified by HPLC, and the corresponding metabolic ratios for CYP1A2, NAT2, and XO were then calculated. Genotyping for NAT2 was performed with standard PCR-RFLP methods. In vitro, with human liver cytosol an inhibition by ibuprofen of the acetylation of sulfamethazine with Ki values between 2.2 and 3.1 mm was observed. Surprisingly, in vivo a significant (P < 0.001) increase of the acetyl-6-formylamino-3-methyluracil/1-methylxanthine (AFMU/1MX) urinary ratio from 0.97 +/- 0.16 to 1.08 +/- 0.18 (95% CI on the difference 0.049, 0.170) was found, indicating an apparent elevation of NAT2 activity. In contrast, no change was observed for the ratios used for XO and CYP1A2. Because an induction of NAT2 could be excluded, an interaction of ibuprofen with the tubular secretion of some of the caffeine metabolites was assumed. To prove this assumption, the in vivo study was repeated with probenecid, a model substrate of the renal OAT system. Again, a prominent elevation of the AFMU/1MX ratio from 0.97 +/- 0.21 to 1.53 +/- 0.35 was found (P < 0.002; 95% CI on the difference 0.237, 0.876), but also the XO ratio 1MU/1MX was significantly (P < 0.0001) increased from 1.34 +/- 0.09 to 2.24 +/- 0.14 (95% CI on difference 0.735, 1.059) due to a reduction of 1MX excretion. Substrates of OAT interact with renal excretion of caffeine metabolites and may falsify NAT2 and XO phenotyping results. Other phenotyping procedures, which are based on urinary metabolic ratios, should also be validated in this respect, especially in patients under polymedication.

N-Acetyltransferases, sulfotransferases and heterocyclic amine activation in the breast.

Heterocyclic amines are mammary carcinogens in rats and their N-hydroxy metabolites are substrates for subsequent metabolic activation by N-acetyltransferases (NAT) and sulfotransferases (SULT) in man. We investigated the expression of these enzymes in human breast tissue and the relationship between NAT genotype and NAT mRNA expression or enzyme activity. Immunohistochemical staining of sections of breast tissue identified expression of NAT1 and NAT2 protein in human mammary epithelial cells, but not in the stroma. We also measured the formation of DNA adducts of the heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in calf thymus DNA after incubation of their promutagenic N-hydroxy metabolites with mammary cytosols prepared from reduction mammoplasty tissue. Experimental observations gained from use of enzyme cofactors and NAT and/or SULT inhibitors on cytosolic enzyme activity, recombinant NAT1 activity and heterocyclic amine-DNA adduct formation suggest that both NAT1 and SULT1A enzymes contribute significantly to the activation of N-hydroxylated heterocyclic amines in mammary tissue. NAT1 mRNA transcript levels were found to be two- to three-fold higher than mRNA transcripts of the NAT2 gene in reduction mammoplasty tissue and mammary epithelial cells. NAT1-specific p-aminobenzoic acid acetylation activity, but not NAT2-specific sulfamethazine acetylation activity, was detectable in mammary cytosols. There was no association apparent between NAT genotype and the levels of NAT mRNA or NAT enzyme activity, or between NAT1 genotype and IQ-DNA adduct formation mediated by mammary cytosols. Western blot analysis of mammary cytosolic protein showed detectable levels of SULT1A1 and SULT1A3.

Single nucleotide polymorphisms, metabolic activation and environmental carcinogenesis: why molecular epidemiologists should think about enzyme expression.

This commentary was written to stimulate thoughts on, and consideration of, enzyme expression data in target organs when investigating possible associations between polymorphisms in carcinogen activation enzymes, lifestyle/dietary factors and cancer risk. The lung and breast are taken as examples. There is overwhelming evidence for a genotoxic mechanism in lung cancer development, and compelling evidence for the contribution of genotoxins to breast cancer aetiology. A consistent association has been shown where lung cancer risk is decreased by a G-->A polymorphism in the myeloperoxidase (MPO) gene, which is expressed in neutrophils recruited to the lung after chemical or immunological insults. In the breast, a consistent lack of association has been observed for women who are fast N:-acetyltransferase type 2 (NAT2) acetylators consuming cooked meat. This could be explained by the lack of detectable NAT2-associated sulfamethazine acetylation activity in cytosols prepared from mammary tissue, suggesting a minor contribution to carcinogen activation. The recent identification in mammary cytosols of detectable sulfotransferase isoforms (SULT1A1 and SULT1A3), which have high catalytic efficiency for activating N:-hydroxylated heterocyclic amines (HCAs, mutagens in cooked meat), offers a more important role for these enzymes in the metabolic activation of genotoxins in the breast. The possible contribution of MPO and lactoperoxidase enzymes to carcinogen activation in mammary tissue is also considered. Sulfotransferases and peroxidases have wide substrate specificity in terms of carcinogen activation (HCAs, aromatic amines and polycyclic aromatic hydrocarbons-all present in cooked meat and tobacco smoke) compared with NATs (HCAs and aromatic amines only). For gene-environment interactions, investigations into functional polymorphisms in SULT and peroxidase genes may, therefore, offer new evidence for the involvement of genotoxins in the initiation of carcinogenesis. Identification of the isoforms (if any) of carcinogen activation enzymes that are expressed in the organs of interest will help to determine which genes to investigate in these studies.

Effect of physical training on sulfamethazine acetylation rate

We studied the rate of sulfamethazine acetylation in athletes and untrained controls aging 18-22 years. The rate of sulfamethazine acetylation in controls was characterized by a bimodal distribution: rapid and slow acetylators constituted 42 and 58%, respectively. The rate of sulfamethazine biotransformation in athletes was characterized by a trimodal distribution: ultrarapid, rapid, and slow xenobiotic acetylators constituted 48.4, 22.6, and 29%, respectively. The ultrarapid acetylation phenotype was probably associated with N-acetyltransferase induction and reflected adaptation to physical exercises

Acetaminophen is an inhibitor of hepatic N-acetyltransferase 2 in vitro and in vivo.

Slow acetylators of the polymorphic N-acetyltransferase 2 (NAT2, EC 2.3.1.5) suffer more often from side-effects of NAT-substrates than fast acetylators. Since concomitant administration of drugs may inhibit NAT2, we studied the influence of acetaminophen on NAT2 in human hepatic cytosol in vitro and in healthy individuals. In-vitro acetylation was assessed in liver homogenate of one fast and one slow acetylator using sulfamethazine as a test substrate. Acetaminophen competitively inhibited sulfamethazine acetylation in fast and slow acetylator liver samples with Ki values of acetaminophen of 2144 micromol/l and 712 micromol/l, respectively. In additional experiments, exposure of human liver cytosol to p-aminophenol, a putative precursor of acetaminophen in this reaction, revealed production of substantial amounts of acetaminophen, which indirectly suggests that acetaminophen may bind to the active site of NAT2. In-vivo acetylation was quantified with a urinary caffeine assay in 20 healthy volunteers at baseline and after repetitive oral administration of 1000 mg acetaminophen every 6 h for 1 day. The ratio of the acetylated caffeine metabolite acetyl-amino-6-formylamino-3-methyluracil to 1-methylxanthine was reduced by 30.9% (range 11.0-50.1%) in fast acetylators (n = 10) and by 19.3% (range 0.2-36.5%) in slow acetylators (n = 10). Acetaminophen, a widely used over-the-counter drug, which shares structural similarities with acetylated products, inhibits NAT2 both in vitro and in vivo. These findings suggest that even compounds which are not metabolized by NAT2 may inhibit the enzyme and reduce its metabolic capacity.

Cytosolic acetylation of sulfamethazine decreases hepatic release of ketone bodies in vivo in fasting rats

The effect of sulfamethazine (SMZ) on ketogenesis was studied in this report. SMZ, a sulfonamide metabolized by cytosolic acetylation in liver, was intraperitoneally injected (2 mmol/kg) to ketamine-anesthetized, overnight-fasted rats. Ketogenesis was measured by the Fick principle from the trans-hepatic (A-V) gradients of acetoacetate (AcAc) and D-β-hydroxybutyrate (gbŌHB). Prior to SMZ injection, A-V gradient of ketone bodies (KB) (AcAc + β-OHB) was −1.38 mM, indicating release from the liver. After SMZ injection, the release of KB decreased rapidly, maintainngg at a level ∼50% less than controls throughout the 2-h experimental period. Plasma concentrations of AcAc and β-OHB also decreased. In contrast, plasma concentrations and trans-hepatic gradients of free fatty acids (FFA) were not significantly affected. Our results thus indicate that SMZ acetylation in liver mobilizes acetyl CoA from mitochondria. Decreased hepatic ketogenesis limits the availability of KB and may thus affect energy metabolism in the extra-hepatic hepatic tissues. The incomplete inhibition on ketogenesis may indicate compartmentation of acetyl CoA in liver mitochondria.

Distribution of acetyltransferase activities in the intestines of rapid and slow acetylator rabbits

Epidemiological studies have shown that there is a significantly greater proportion of the rapid acetylator phenotype in patients with colorectal tumors than in controls; phenotype-related differences in bioactivation of dietary or environmental amines in the intestinal epithelium have been suggested as a mechanism for this effect. In the present study, we have used hepatic and intestinal cytosols to compare N-acetyltransferase (NAT1 and NAT2), O-acetyltransferase (OAT) and arylhydroxamic acid N,O-acyltransferase (AHAT) distribution in rapid and slow acetylator rabbits. The ratio (rapid/slow) for p-aminobenzoic acid acetylation (a selective substrate for NAT1) was 6 in liver, 1.7-2 in small intestine and 1.3-1.5 in large intestine while the ratio of sulfamethazine acetylation (a selective substrate for NAT2) was 150 in liver, 16-22 in small intestine and 1.8-2.5 in large intestine. The ratios (rapid/slow) for DNA binding of N-hydroxy-3,2'-dimethyl-4-aminobiphenyl and N-hydroxy-4-aminobiphenyl (primarily substrates for OAT) were 82-84 in liver, 13-20 in small intestine and 3.8-5.3 in large intestine and for DNA binding of N-hydroxy-2-acetylamidofluorene (a substrate for AHAT), the ratio was 432 in liver, 32-161 in small intestine and 8.8-13.5 in large intestine. The data show also that NAT1 activity is uniformly distributed along the intestinal tract whereas NAT2 activity is highest in the small intestine. In addition, hepatic and intestinal OAT and AHAT but not NAT1 activities in the rabbit intestine are similarly distributed to activities for NAT2, suggesting that NAT2, OAT and AHAT activities are properties of a single protein in the rapid acetylator phenotype. Moreover, OAT and AHAT activities were much higher in tissues from the rapid than the slow phenotype. The data support the hypothesis that phenotype-dependent metabolic activation of N-OH heterocyclic or aromatic amines to reactive acetoxy metabolites may be involved in the etiology of colorectal cancer.

Acetylation pharmacogenetics. The slow acetylator phenotype is caused by decreased or absent arylamine N-acetyltransferase in human liver.

The biochemical basis underlying the genetic polymorphism of drug N-acetylation was investigated using a combination of in vivo and in vitro assays for arylamine N-acetyltransferase (NAT) activity and content in human liver. The acetylator phenotype of 26 surgical patients was determined using caffeine as an innocuous probe drug by measurement of the 5-acetyl-amino-6-formylamino-3-methyluracil to 1-methylxanthine molar ratio in urine. Liver wedge biopsies from these patients and livers from 24 organ donors were then used for measurement of N-acetyltransferase activity with the substrate sulfamethazine and for quantitation of immunoreactive N-acetyl-transferase protein. In vivo (caffeine metabolites in urine) and in vitro (sulfamethazine acetylation) measures of N-acetyl-transferase activity correlated very highly (r = 0.98). Moreover, in all subjects tested, slow acetylation both in vivo and in vitro was associated with a decrease in the quantity of immunodetectable N-acetyltransferase protein in liver cytosol relative to that seen in cytosols from rapid acetylator livers. Two kinetically distinct enzyme activities, designated NAT-1 and NAT-2, were partially purified from low- and high-activity livers and their relationship to acetylator status was determined. Low acetylation capacity was related to decreases in the liver content of both of these immunologically related proteins. The results demonstrate that genetically defective arylamine N-acetylation is due to a parallel decrease in the quantity of two structurally and functionally similar acetylating enzymes.

Comparison of hepatic drug metabolizing enzyme activities in several agricultural species

1. 1. Several pathways of drug metabolizing enzyme activity were measured in hepatic fractions of cattle, sheep, goats, chickens, turkeys, ducks, rabbits and rats. The pathways examined included the O-demethylation of p-nitrophenol, microsomal ester hydrolysis of procaine and glucuronidation of p-nitrophenol, and the cytosolic acetylation of sulfamethazine and sulfation of 2-naphthol. 2. 2. For most enzymatic pathways measured, goats were more similar to sheep (wether) than to cattle (steers). The exception was UDP-glucuronyltransferase activity, which was significantly higher for the goat than for any other species studied. 3. 3. Within the avian subset, the chicken and turkey were usually the most similar species. 4. 4. The activities of arylsulfotransferase isozymes III and IV were particularly low for the duck compared to the chicken and turkey. 5. 5. N-acetyltransferase activity was very high for rabbits and very low for sheep and goats.

Hepatic drug metabolizing enzyme activity in the channel catfish, Ictalurus punctatus

1. Several pathways of drug metabolizing enzymic activity were measured in hepatic fractions of the channel catfish and rat using model substrates. The pathways examined included the O-demethylation of p-nitroanisole, microsomal ester hydrolysis of procaine and glucuronidation of p-nitrophenol, and the cytosolic acetylation of sulfamethazine and sulfation of 2-naphthol. Catfish liver preparations were incubated at both 25°C and 37°C. 2. The oxidative metabolism of p-nitrophenol was only one-eighth that of the rat at 37°C and one-twelfth that of the rat at 25°C. 3. Procaine ester hydrolysis was negligible in catfish microsomal preparations. 4. At 37°C, p-nitrophenol glucuronidation was equivalent in catfish and rat microsomes. 5. Catfish cytosolic preparations exhibited N-acetyltransferase and arylsulfotransferase nearly comparable to those of the rat. 6. Rates of glucuronidation and sulfation were higher at 37°C than at 25°C in hepatic fractions of catfish.

An alternative test for acetylator phenotyping with caffeine.

Previously published methods allow the determination of the genetically controlled acetylator status using caffeine as a test drug, based on the urinary excretion of a ring-opened metabolite of caffeine, an acetylated uracil (5-acetylamino-6-formylamino-3-methyluracil). 5-Acetylamino-6-formylamino-3-methyluracil is labile but can be converted into a stable, deformylated product referred to as 5-acetylamino-6-amino-3-methyluracil, which has recently been shown to be quantifiable by exclusion chromatography. The first part of the present article represents a longitudinal study of three subjects to assess the intraindividual variability of those caffeine metabolite ratios that are of potential interest for the determination of acetylator phenotypes. Effects of single and multiple doses, as well as of different periods of urine collection, were tested. A ratio relating the excretion of 5-acetylamino-6-amino-3-methyluracil to that of all products of the 7-demethylation pathway of paraxanthine proved to be highly reproducible, particularly after collection of overnight urine after coffee consumption during the day. This ratio showed complete concordance with the plasma index for sulfamethazine acetylation. The second part of this article showed the use of this ratio in a population study. It allowed a good separation of slow and fast acetylators and probably also a separation of homozygous and heterozygous fast acetylators.

No effect of smoking on sulfamethazine acetylation.

Seven healthy subjects who smoked at least one pack of cigarettes/d were acetylator-phenotyped with sulfamethazine (SMZ) while they were actively smoking, and again at least one month after they had completely stopped. There were no significant differences of the acetylation profiles in the smoking vs. nonsmoking state, as measured by %ASMZ in serum six hours post-SMZ dosing or by %ASMZ in urine five to six hours post-SMZ dosing. We conclude that smoking does not influence SMZ acetylation and probably does not affect drug acetylation in general.

Polymorphic N-acetylation of a caffeine metabolite.

In the course of investigations into variability in the metabolism of caffeine in human populations, urinary levels of 5-acetylamino-6-formylamino-3-methyluracil (AFMU), a newly discovered ring-opened metabolite of caffeine, were found to be both bimodally distributed and interethnically variable in samples (Caucasian: n = 42; Oriental: n = 26) from the Toronto population. To test the premise that the polymorphic N-acetyltransferase enzyme (E.C.2.3.1.5) could be responsible for the production of AFMU, 20 of the subjects were phenotyped for acetylator status using sulfamethazine (SMZ). Concordance for all subjects between AFMU production and SMZ acetylation strongly suggests that the acetylation polymorphism is involved in the formation of AFMU in man.

Acetylation of p-aminobenzoic acid by human blood

Acetylation of p-aminobenzoic acid was studied in human blood cell lysates. The rate of acetylation with acetyl-coenzyme A was 3.4 nmoles per min per 0.5 ml lysate (corresponding to 0.5 ml blood with a 50% hematocrit). In the presence of a coenzyme A generating system, the rate was only 0.1 nmole per min per 0.5 ml lysate. N-Acetyltransferase (acetyl-CoA : arylamine N-acetyltransferase, EC 2.3.1.5) activity exhibited a temperature optimum within the range of 34–37° with a Q 10of 2 between 24–34°. Heating for 3 min at 50° caused 50 per cent inactivation of enzymatic activity. The pH activity profile showed an optimum at pH 6.0–6.5. p-Chloromercuribenzoate was a potent inhibitor causing 50 per cent inhibition at 9 μM. The apparent K m value for p-aminobenzoic acid was 0.4 mM and for acetylcoenzyme A, 0.3 mM. The enzyme activity with p-aminosalicyclic acid was about 50 per cent that obtained with p-aminobenzoic acid. Acetylation of sulfamethazine was either very low or in several individuals undetectable. Isonicotinic acid hydrazide at a concentration 10 times that of p-aminobenzoic acid did not interfere with acetylation of the latter, nor did trimethoprim, another compound with an amine moiety. Folic acid and amethopterin competitively inhibited the acetylation of p-aminobenzoic acid, with respective K i values of 0.01 mM and 0.06 mM. It is concluded that the activity of N-acetyltransferase in human blood may have important clinical implications.

Polymorphic acetylation of sulfamethazine in a Nigerian (Yoruba) population.

1. Sulfamehtazine was administered orally to 165 Yoruba subjects (40 mg/kg body wt.). Free and acetylated sulfamethazine were determined in the 6 h urines. 2. The population frequency histogram for percentage of urinary acetylated sulfamethazine was bimodal, although not completely resolved. Slow acetylators constituted 45% of the population studied. 3. This Yoruba population did not differ statistically (P greater than 0.05) in this respect from the two major tribally distinct groups in Nigeria previously investigated.

Kinetic discrimination of three sulfamethazine acetylation phenotypes.

The relationship between sulfamethazine disposition kinetics and acetylator phenotype was studied in 19 healthy subjects. Various kinetic parameters for sulfamethazine and its N4-acetylated metabolite were determined after a dose of a rapidly absorbed oral solution. When plotted on a frequency distribution histogram, the results exhibited a well-defined trimodal pattern for acetylation clearance values and overall elimination or metabolic rate constants. These data were consistent with the well-recognized acetylation polymorphism for sulfamethazine, except that they clearly subdivided the previously acknowledged "fast" acetylator mode into intermediate and rapid acetylator groups. The apparent distribution volume and renal clearance for sulfamethazine and acetylsulfamethazine did not differ significantly among the 3 phenotypes. Of special interest was the observation that rapid acetylators initially produce much greater amounts of acetyl metabolite than intermediate acetylators. The potential clinical implications of identifying rapid and intermediate acetylators are discussed in view of evidence showing that acetyl metabolites may be pharmacologically active or function as intermediates in toxic metabolic pathways.

Acetylation of sulfamethazine in a Nigerian population.

Sulfamethazine (syn, sulfadimidine) is inactivated by conversion to its N-acetyl derivative. Individuals are phenotyped as either "rapid" or "slow" acetylators. We have tested the validity of this theory in a Nigerian population. The frequency distribution histograms of the percentage acetylsulfamethazine in urine and serum were found to be bimodal, indicating the existence of a genetic polymorphism as observed by earlier workers. A plot of the percentage of the drug acetylated in serum against that in urine of the same individual results in a satisfactory separation of the rapid and slow acetylator phenotypes. An incidence of the slow acetylator phenotype of 41% was observed in the Nigerian population tested. How this observation fits into the hypothesis that the slow frequency of the allele increases from the Arctic Circle toward the Equator is discussed.