HPLC直接进样测定咖啡因代谢物评价三种药物代谢酶活性

目的：建立测定尿中咖啡因的5种主要代谢物：5-乙酰氨基-6-甲酰氨基-3-甲基尿酸（AFMU）、1-甲基尿酸（1U）、1-甲基黄嘌呤（1X）、1，7-二甲基尿酸（17U）和1，7-二甲基黄嘌呤（17X）的高效液相色谱法，以评价N-乙酰基转移酶（NAT2）、细胞色素P450酶1A2（CYP1A2）和黄嘌呤氧化酶（XO）三种药物代谢酶的活性。方法：采用反相高效液相梯度洗脱法直接进样测定尿液内咖啡因代谢产物AFMU、1U、1X、17U和17X的相对含量，计算AFMU／（AFMU＋1X＋1U）、（AFMU＋1X＋1U）／17U和1U／（1X＋1U），绘制概率分布直方图，分别反映NAT2、CYP1A2和XO的活性。结果：NAT2活性呈两态分布，快、慢乙酰化代谢表型的临界点为0．26，CYP1A2和XO酶活性呈近似正态分布。结论：本方法简便、准确、快速，适合于尿中咖啡因代谢物的测定及NAT2、CYP1A2和XO等药物代谢酶活性的研究。     

咖啡因代探针研究乙酰化代谢表型与膀胱癌关系

目的 以咖啡因为代谢探针，研究膀胱癌发生发展的N－乙酰化代谢表型分布的统计学相关性。方法 根据人尿液中咖啡因代谢物5－乙酰氨基－6－甲酰氨基－3－甲基尿嘧啶（AFMU）和甲磺嘌呤1X）的高比值绘制概率分布直方图和概率单位图，寻找区分快慢乙酰化代谢表型的截点，确定人的乙酰化代谢表型分布。结果 健康志愿和膀胱癌患概率分布直方图和概率单位图呈明显多态性，截点为1.10，即大于1.10为快乙酰化代谢表型，小于1.10为慢乙酰化代谢表型，健康志愿中快、慢人乙酰化表型分别为149例（73.7%）和54例（26.3%）。膀胱癌患分别为36例（53.7%）和31例（46.3），两存在显统计学差异（P＜0.01）。志愿和膀胱癌患基因频率分别为0.51和0.68，优势比为2.376(95%可信区间为1.3513和4.1776）。结论 中国人乙酰化代谢表型分布呈多型性。慢乙酰化代谢表型个体可能为膀胱癌多发和易感人群。     

咖啡因探针法测定正常人肝脏药物代谢酶CYP1A2活性

目的:建立咖啡因4种主要代谢物含量的测定方法,探讨咖啡因代谢物在药物代谢酶CYP1A2活性评价中的意义。方法:采用反相高效液相梯度洗脱法测定尿液内咖啡因代谢产物5—乙酰氨基—6—甲酰氨基—3—甲基尿酸(AFMU)、1—甲基尿酸(1U)、1—甲基黄嘌呤(1X)和1,7—二甲基尿酸(17U)的相对含量,计算代谢物比率(AFMU+1X+1U)/17U,绘制频数分布直方图,评价CYP1A2活性。结果:受试者代谢物比率平均值为4.27,呈正态分布。结论:本方法简便、准确、快速,适合于尿液中咖啡因代谢物的测定及CYP1A2活性的研究。     

妊娠妇女乙酰化代谢表型的研究

目的：探讨胎盘乙酰基转移酶对妊娠和妊娠高血压综合征妇女乙酰化代谢表型的影响。方法：采用HPLC法测定尿液内咖啡因代谢产物5—乙酰氨基—6-甲酰氨基—3—甲基尿密啶(AFMU）和甲黄嘌呤(1X)的相对含量，计算二峰面积比(PAR)，绘制概率分布直方图，确定健康妇女快、慢乙酰化代谢表型的临界点(截点)，评价健康妇女，妊娠妇女，妊娠高血压综合征妇女乙酰化代谢表型的分布特点。结果：健康妇女快、慢乙酰化代谢表型的截点为1.05。妊娠妇女和妊高征妇女快乙酰化代谢表型频率分别为84．8％和92．9％，显高于健康妇女的72％(P＜0．05)。妊高征妇女尿蛋白阳性与阴性乙酰化代谢表型分布的差异无统计学意义(P＞0．10)，尿蛋白阳性AFMU／1X值显低于阴性(P＜0．01)。结论：胎盘乙酰基转移酶影响妊娠妇女乙酰化代谢，进而影响其表型分布。常规测定妊娠妇女乙酰化代谢表型，可为临床用药提供依据。     

测定咖啡因代谢物评价 N-乙酰转移酶、CYP1A2和黄嘌呤氧化酶活性

目的是对中国人N-乙酰化酶(NAT2)、CYP1A2酶和黄嘌呤氧化酶(XO)的活性进行分析。120名健康志愿者饮用3杯咖啡后于4～5h留尿,用HPLC方法测定尿中5种咖啡因主要代谢物浓度,即5-乙酰胺基-6-甲酰胺基-3-甲基尿嘧啶(AFMU)、1-甲基黄嘌呤(1X)、1-甲基尿酸(1U)、1,7-二甲基尿酸(17X)、1,7-二甲基黄嘌呤(17U)。其中N-乙酰化酶活性用AFMU/1X或AFMU/(AFMU+1X+1U)表示;CYP1A2酶活性指标采用(AFMU+1X+1U)/17X或AFMU+1X+1U)/17U;XO酶活性指标采用1U/1X或1U/(1X+1U)。结果表明,N-乙酰化酶活性呈两态分布,慢代谢者占16.7%,CYP1A2和XO酶活性呈对数正态分布,其代谢比值与国外文献报道一致。提示通过测定咖啡因代谢物比值,可以进行NAT2酶、CYP1A2酶和黄嘌呤氧化酶活性分析。     

3-季胺头孢菌素DQ-2556在大鼠和兔中的药动学及其剂量依赖性

在C－7位上有2一氨基喀哇和甲氧亚氨基团的大多数头孢菌素抗生素，如头孢喀脂、头抱哇胀和头抱曲松等对G”和G菌（除绿脓杆菌外）有显著的抗菌活性。某些C－3位上有卜毗咤基团的头抱菌素，如头抱他咤则对绿脓杆菌有抗菌活性。一种新的3一季胺头抱菌素DQ－2556［（6R7R）－7－［（Z）2－（2一氨基峻哇一个基卜2－（甲氧氨基）乙酸胺基）‘－344－（倾吐一5基）－l一毗吐基］甲基］－8一氧代一5一疏一卜氮杂二环［4，2，0伴一2一烯一2－＆酸酯］在分子结构中兼有上述两个特点，且具有包括对绿脓杆菌在内的广谱抗菌活性。现已报道，DQ－25…     

4-甲基-1.3-二氢-2H-咪唑-2-酮合成方法改进

4一甲基一13－H氢一ZH一咪娃一2一阴（I）是一种治疗心力衰竭药物5一取代一4一甲基一1．3－H氢一ZH一咪哇一2一酮类药物的重要中间体！’］，有多种合成方法，分别以乙酸乙酸乙酸、p一羟基丙胺、氨基乙酸为原料，经过不同的化学反应制得氨基丙酮（Ill），然后和氨酸钾作用进行环会反应制得（l）。在本文，我们则选择以环氧丙烷为原料经加成，氧化得l一氯丙酮（11），再定位氨化向样得到氨基丙团（Ill）．然后与尿素进行环会反应，使得到（l）．新的合成路线用反应式表示如下．实验部分在装有搅拌器、摄度计和回流冷反管的250Inl三口瓶中…     

高效液相色谱法测定尿中咖啡因主要代谢物浓度

本文建立了测定尿中咖啡因5种主要代谢物（AFMU、1X、1U、17X、17U）浓度的高效波相色谱法。尿样用硫酸铵饱和后加氯仿及异丙醇混合液（85：15）提取2次，空气流吹干，蒸馏水溶解进样。以ShimPackC18为固定相，甲醇-动腈-0．05％醋酸（10：1：89）为流动相，扑热息痛为内标，流速为1．2ml／min，在280um处定量检测。本法精确稳定可靠。用此方法测定了120名健康志愿者口服咖啡后的尿样，对人体内N-乙酰化转移酶和CYP1A2酶活性作了初步分析。     

传统抗凝剂肝素的其它治疗作用

肝素及硫酸乙酸肝素（HS）在氨基葡聚精族中存在很大生物学差异。1肝素及HS的化学组成和细胞定位HS及肝素链常发软附干核蛋白中心的丝氨酸残基上。化学合成的肝素是D－葡糖酵酸呈1，4与，乙酸－D－氨基葡聚糖连接的二糖交替连接物。修改后的生物合成程序是：（1）N－乙酸－D－氨基葡聚糖脱乙酸化后，此氨基重新硫酸化；（2）D－葡糖醛酸C5差向异构化为L－艾杜糖醛酸；（3）主要在L－艾杜糖醛酸和D一氨基葡聚糖残基上的CZ及C6位氧一硫酸化2（4）在D一葡糖醛酸和D一氨基葡糖残基上的C。及C3位氧分别一硫酸化则是次要的。HS生物合成…     

藏药佐太对大鼠CYP1A2和NAT2活性的影响

目的:研究藏药佐太对大鼠细胞色素氧化酶(CYP1A2)、药物代谢酶N-乙酰基转移酶2(NAT2)活性的影响。方法:将70只SD大鼠随机均分为正常对照(生理盐水)组和佐太低、中、高剂量(1.2、3.8、12 mg/kg)单次给药组和多次给药组(每天1次,连续12 d),分别ig给药。正常对照组、佐太单次给药组于第2天,佐太多次给药组于第13天分别ig给予咖啡因(25 mg/kg),5 h后采集尿液,按10 mg/ml加入维生素C。采用高效液相色谱法测定大鼠尿液中咖啡因代谢物5-乙酰氨基-6-甲酰氨基-3-甲基尿酸(AFMU)、1-甲基黄嘌呤(1X)、1-甲基尿酸(1U)、1,7-二甲基尿酸(17U)的含量,以(AFMU+1X+1U)/17U、AFMU/(AFMU+1X+1U)比值来反映CYP1A2和NAT2活性。结果:与正常对照组比较,佐太中剂量单次给药组及多次给药组、高剂量多次给药组大鼠(AFMU+1X+1U)/17U、AFMU/(AFMU+1X+1U)比值降低,即CYP1A2和NAT2活性降低,差异有统计学意义(P<0.05)。结论:佐太对大鼠CYP1A2和NAT2活性有明显抑制作用。     

汉族儿童N—乙酰化代谢表型分布及其与21—三体综合征和假肥大性肌营养不良症相关性研究

目的 以咖啡因为代谢探针，研究汉族儿童Ｎ－乙酰化代谢表型分布规律及其与２１－三体综合征（ＤＳ）和假肥大性肌营养不良症（ＤＭＤ）相关性。方法 根据参试者尿中咖啡因代谢物５－乙酰氨基－６－甲酰氨基－３－甲基尿嘧啶（ＡＦＭＵ）和甲磺嘌呤（１Ｘ）峰高比的对数值（１ｇＡＦＭＵ／１Ｘ）绘制频率分布直方图，寻找区分快、慢乙酰化代谢表型的截点，确定患儿和健康儿童的Ｎ－乙酰化代谢表型分布。结果 正常儿童乙酰化代谢表型分布直方图呈双态性，截点明显，为 ０．２５（ｌｇＡＦＭＵ／１Ｘ），慢乙酰化代谢表型个体为１６．９％，而 ＤＳ和ＤＭＤ患儿则分别为４１．９％和５０％（ｘ２分别为８．２８７和１１．３８７，Ｐ＜０．０５）。男、女和＞６岁与≤６岁儿童快、慢乙酰化代谢表型分布差异无显著性。结论 汉族儿童乙酰化代谢表型分布呈多态性，与成人相似。年龄和性别对结果无显著影响。     

Determination of N-acetylation phenotyping in a Greek population using caffeine as a metabolic probe.

Studies of isoniazid, the well known antituberculosis drug, have revealed that N-acetylation polymorphism, is of great clinical importance. In humans, N-acetylation is one of the most important pathways in the inactivation of isoniazid. Caffeine, which is also biotransformed by N-acetylation, has been widely used as an in vivo probe for the assessment of N-acetyltransferase polymorphism. The activity of N-acetyltransferase can be estimated from the urinary metabolic ratio of two caffeine metabolites, namely, 5-acetylamino-6-formylamino-3-methyluracil (AFMU), and 1-methylxanthine (1X) after the ingestion of caffeine. In the present study caffeine was used as a metabolic probe to determine N-acetyltransferase polymorphism in 83 healthy Greek volunteers by means of the molar ratio of AFMU and IX determined in urine following ingestion of 200 mg caffeine. Frequency distribution analysis of the metabolic ratios AFMU/1X revealed two distinct groups with 66.3% (n = 55) slow acetylators and 33.7 % (n = 28) rapid acetylators. No statistically significant difference was detected between slow and fast acetylators in terms of gender, smoking habits and caffeine-intake habits. These results are in agreement with previous studies on N-acetyltransferase activity in Caucasians using caffeine as a metabolic probe. They also agree with reports on N-acetyltransferase activity in Greek tuberculosis patients using isoniazid as a metabolic probe. Thus, the use of caffeine as a metabolic probe is a reliable method for the assessment of N-acetyltransferase activity in the Greek population.     

NAT2 and CYP1A2 phenotyping with caffeine: head-to-head comparison of AFMU vs. AAMU in the urine metabolite ratios

AIMS: (i) To compare the phenotyping of healthy subjects for NAT2 and CYP1A2 activities with caffeine, by the simultaneous assay of the urinary metabolites AFMU and AAMU, and (ii) to ascertain whether NAT2 and CYP1A2 phenotyping is influenced by the use of AFMU or AAMU in the metabolite ratio. METHODS: Thirty-five healthy subjects (16 men, 19 women) participated to the study. Caffeine metabolite concentrations were measured in urine collected 8 h after 2.5 mg kg-1 caffeine intake using a new validated h.p.l.c. method. The metabolite ratios AFMU/1X, AFMU/(AFMU+1X+1U), AAMU/1X, AAMU/(AAMU+1X+1 U), and (AFMU+1U+1X)/17U, (AAMU+1U+1X)/17U were determined as indices of NAT2 and CYP1A2 activity, respectively. RESULTS: Slow and rapid acetylators were similarly identified using the four NAT2 metabolite ratios in 139 out of 140 measurements. An appreciable amount of AAMU was present in urine that was immediately acidified and analysed. Consequently, the ratio using AFMU was lower than that using total AAMU following transformation of AFMU in basic conditions. The proportion of AFMU in urine analysed immediately expressed as AFMU/(AFMU+AAMU) ratio did not correlate with urine pH, but was a function of the acetylation phenotype, with a low intergroup variability (64 +/- 3% and 32 +/- 5%, for rapid and slow acetylators, respectively; P < 0.00001, anova). Regarding CYP1A2 activity, a good correlation (r = 0.99) was observed between the metabolite ratios calculated from AFMU and AAMU, although the ratios calculated from AFMU were proportionately and systematically lower P < 0.00001, paired t-test, slope 1.2). CONCLUSIONS: This study demonstrates that both AFMU and AAMU can be used for NAT2 and CYP1A2 metabolite ratio determinations. The reported conversion of AFMU into AAMU is unlikely to explain the large amount of AAMU in urine that was acidified and analysed immediately after voiding. The results suggest that AAMU is formed not solely through a nonenzymatic hydrolysis in urine, but in vivo by a NAT2 phenotype-dependent pathway.     

Determination of acetylator phenotype in Caucasians with caffeine

Summary Acetylator status in 595 healthy Caucasian volunteers was determined with caffeine. The test group consisted of 372 males and 223 females, 18 to 78 years of age. 312 volunteers were smokers. Caffeine was taken orally as Coffein Comprette (200 mg caffeine × H₂O) and urine was collected for 8 h. The metabolic ratio (MR) of 5-acetylamino-6-formylamino-1-methyluracil (AFMU) to 1-methyl-xanthine (MX) was determined by HPLC.In total 61.7% of the group had a MR<0.48 and were classified as slow acetylators. MR varied from 0.01 to 0.47 in the slow acetylators and from 0.48 to 4.7 in the fast acetylator group. Clear dependence of acetylator type upon age, sex or smoking behaviour was not observed.The present study has confirmed the caffeine test as a feasible tool to determine acetylation capacity.     

Relationship between the severity of alcoholic liver cirrhosis and the metabolism of caffeine in 226 patients

OBJECTIVES: To evaluate the polygenic regulated caffeine metabolism in a group of 226 patients with liver alcoholic cirrhosis classified according to the Child score. METHODS: Over a 14-year period an hepatic function test, using caffeine as probe drug, has been systematically associated to the usual clinical and biochemical investigations performed in patients with liver alcoholic cirrhosis. "Caffeine test" consisted in a 200 mg caffeine oral intake. Urines were collected over 24 hours: caffeine (137X), 1-7 dimethylxanthine (17X), 1-3 dimethylxanthine (13X), 1-3 dimethylurate (13U), 3-7 dimethylxanthine (37X), 1-7 dimethylurate (17U), 1-methylxanthine (1X), 1-methylurate (1U), 7-methylxanthine (7X), 3-methylxanthine (3X), and 5-acetylamino-6-formylamino-3-methyluracyl (AFMU) were analyzed by high performance liquid chromatography (HPLC). Total and individual metabolite urinary elimination rates were expressed in micromol/24 hours. Enzyme activities were evaluated from the following urinary metabolites ratios: (AFMU+1U+1X)/17U for CYPIA2, 17U/17X for CYP2A6, AFMU/(AFMU+ 1U+1X) for NAT-2, 1U/1X for XO. RESULTS: Compared to healthy subjects, whatever the Child score, caffeine metabolism was reduced by half in patients with alcoholic cirrhosis. The main cause was the decreased CYP1A2 activity. On the other hand, XO and CYP2A6 activities were increased and NAT-2 activity remained unchanged in slow acetylators (SA) and decreased in rapid acetylators (RA) Child B and C. Bimodality of NAT-2 distribution was unclear, but a right assignment of RA and SA phenotype in cirrhotic patients, confirmed by comparison with genotype, was obtained, using the antimode value of NAT-2 distribution used in healthy subjects. At last, there was an interindividual variability in caffeine metabolism as great as in the usual laboratory parameters. CONCLUSION: Metabolism of caffeine is decreased in patients with alcoholic liver cirrhosis. This decrease paralleled the modifications of the usual laboratory tests and does not bring additional information on the severity of the disease. But the equilibrium between the various metabolic pathways of caffeine is impaired. Beyond the changes of a specific enzymatic activity, this must be taken into account particularly for drugs whose metabolism is of the polygenic regulation type.     

Pharmacokinetics, N1-glucuronidation, and N4-acetylation of sulfa-6-monomethoxine in humans

Sulfamonomethoxine (S) is metabolized by O-dealkylation, N4-acetylation, and N1-glucuronidation. In humans, only N1-glucuronidation (12%) and N4-acetylation (36%) takes place. The N1-glucuronide is directly measured by HPLC. When N4-acetylsulfamonomethoxine (N4) is administered as the parent drug, N1-glucuronidation does not occur. After an oral dose, fast and slow acetylators show a similar t1/2 for S (25.0 +/- 4.6 hr vs. 29.8 +/- 4.8 hr; p = 0.459), and the t1/2 of the N4-acetyl conjugate is also similar in fast and slow acetylators (25.0 +/- 4.64 hr vs. 29.8 +/- 4.8 hr, p = 0.459). The intrinsic mean residence time of N4 is 7.1 +/- 2.3 hr. The mean total body clearance of S is 5.0 +/- 1.3 ml/min, the renal clearance is 0.84 +/- 0.26 ml/min, and the volume of distribution at steady state is 11.7 +/- 3.4 liters. The renal clearance of N4 is 17.89 +/- 4.19 ml/min. No measurable concentrations of the N1-glucuronide of S are found in plasma. The protein binding of S is 92%. N1-glucuronidation results in an 80% reduction in the protein binding of S (11%). N4 shows a high protein binding of 98%. Approximately 60% of the oral dose of S is excreted in the urine.     

Modulation of DNA and protein adducts in smokers by genetic polymorphisms in GSTM1,GSTT1, NAT1 and NAT2

The formation of DNA and protein adducts by environmental pollutants is modulated by host polymorphisms in genes that encode metabolizing enzymes. In our study on 67 smokers, aromatic-DNA adduct levels were examined by nuclease P1 enriched 32P-postlabelling in mononuclear blood cells (MNC) and 4-aminobiphenyl-haemoglobin adducts (4-ABP-Hb) by gas chromatography-mass spectroscopy. Genetic polymorphisms in glutathione S-transferase M1 (GSTM1), T1 (GSTT1) and N-acetyl-transferase 1 (NAT1) and 2 (NAT2) were assessed by polymerase chain reaction-based methods. DNA adduct levels, adjusted for the amount of cigarettes smoked per day, were higher in GSTM1(-/-) individuals (1.30 +/- 0.57 adducts per 108 nucleotides) than in GSTM1(+) subjects (1.03 +/- 0.56, P = 0.05), higher in NAT1 slow acetylators (1.58 +/- 0.54) than in NAT1 fast acetylators (1.11 +/- 0.58, P = 0.05) and were also found to be associated with the NAT2 acetylator status (1.29 +/- 0.64 and 1.03 +/- 0.46, respectively, for slow and fast acetylators, P = 0.06). An effect of GSTT1 was only found in combination with the NAT2 genotype; individuals with the GSTT1(-/-) and NAT2-slow genotype contained higher adduct levels (1.80 +/- 0.68) compared to GSTT1(+)/NAT2 fast individuals (0.96 +/- 0.36). Highest DNA adduct levels were observed in slow acetylators for both NAT1 and NAT2 also lacking the GSTM1 gene (2.03 +/- 0.17), and lowest in GSTM1(+) subjects with the fast acetylator genotype for both NAT1 and NAT2 (0.91 +/- 0.45, P = 0.01). No overall effects of genotypes were observed on 4-ABP-Hb levels. However, in subjects smoking less than 25 cigarettes per day, 4-ABP-Hb levels were higher in NAT2 slow acetylators (0.23 +/- 0.10 ng/g Hb) compared to fast acetylators (0.15 +/- 0.07, P = 0.03). These results provide further evidence for the combined effects of genetic polymorphisms in GSTM1, GSTT1, NAT1 and NAT2 on DNA and protein adduct formation in smoking individuals and indicate that, due to the complex carcinogen exposure, simultaneous assessment of multiple genotypes may identify individuals at higher cancer risk.     

Verified predominance of slow acetylator phenotype N-acetyltransferase 2 (NAT2) in a Hmong population residing in Minnesota

Southeast Asians known as the Hmong have a high prevalence of tuberculosis and select cancers. The slow acetylation (SA) phenotype for N-acetyltransferase 2 (NAT2) has been associated with toxicity from the anti-tuberculosis drug, isoniazid and in increased risk of select cancers. Previous research indicates a 74.5% prevalence of SA in Hmong which differs from other Asian populations including the Japanese and Thai (range: 7%-45%). Given this contrast, the purpose of this study was to confirm or refute this unexpected predominance of the SA phenotype in Hmong. Unrelated, Minnesota Hmong between 18 and 65 years of age consented and participated by ingesting caffeine as the probe for NAT2. A urinary caffeine metabolic ratio AFMU/1X (<0.6) was used to classify subjects as slow acetylators. Among 51 analysable samples provided by 61 enrollees (27 male, 33 female, 1 sex unknown, age 30+/-11 years [mean+/-SD]) there were 47 (92.2%) slow and 4 (7.8%) rapid acetylators. The prevalence of the SA phenotype (92.2%) from this study exceeds the 74.5% (p<0.02 by chi-square test) previously noted in Minnesota Hmong (n=98). The predominance of the SA phenotype within Minnesota Hmong is confirmed. Further studies evaluating this unexpected prevalence, its genetic basis and potential clinical relevance to drug toxicity and disease are warranted.     

N-acetylation polymorphism and diabetes mellitus among Saudi Arabians.

The acetylator phenotypes of 200 Saudi diabetics and an equal number of control subjects of the same origin were determined by measuring the peak height ratio of two urinary caffeine metabolites, 5-acetylamino-6-formylamino-3-methyluracil (AFMU) and 1-methylxanthine (1MX), using a simplified high-performance liquid chromatographic method. Urine samples were collected from the diabetics and the control subjects who regularly drink coffee, tea, or caffeinated beverages as part of their normal daily diet. The patients were classified as either type 1 (insulin-dependent) (28 patients) or type 2 (insulin-independent) diabetics (172 patients) according to standard criteria. The reproducibility of acetylator phenotype was established by examining the peak height ratio of AFMU/1MX in 18 diabetics and 6 control subjects on different days. Significant differences in the proportion of rapid acetylators were observed between type 1 (53.6%) and type 2 (33.7%) diabetics (P < or = .0436), and between the control group (26%) and the overall diabetics (36.5%) (P < or = .024) or those with type 1 disease (P < or = .0028). Also, there was a significant (P < or = .0436) association between rapid acetylator status and type 1 diabetes mellitus.