【文章內(nèi)容簡介】 oxylamines (羥胺 ). The formation of hydroxylamines may account for the toxicity of many aromatic amines. FMO、 CYP－ 450 and MAO NOxidation NC H3C H3R R NC H3C H3ONRNROR 39。NRHR 39。NRO HR N H2R N H O H N OR R N O 2no α hydrogen Reversible 可逆 Tertiary amines Guahidine（ 呱乙啶 ） NN HHN N H 2NN HHN N H 2Ostable Tertiary amines Dapsone（氨苯砜） s o 2H 2 N N H 2 s o 2H 2 N N H O H抗麻風(fēng)藥 no α hydrogen The mechanism which some aromatic prime and secondary amines oxide to effect toxicity RNR 39。HRNR 39。O HX+RNR 39。O XY O XRNR 39。YHB :B+HRHNR 39。YX = S O3, A c Acetaminofluorene (2－乙酰氨基芴 ) N H C O C H 3 N C O C H3O HN C O C H 3O S O 3N C O C H 3 N H C O C H 3N u III. ODealkylation of ethers ? Oxidative Odealkylation of ethers is a mon metabolic reaction. ? The majority of ether groups in drug molecules are aromatic ethers. ? These ethers are oxidized by liver microsomal oxidases. The mechanism of Odealkylation ? The mechanism of dealkylation is analogous to that of Ndealkylation, oxidation of the αcarbon, and subsequent deposition of the relatively unstable gem diol. The substituent alkyl group leaves as a carbonyl derivative. R O C H 2 R 39。 R O C H R 39。 R O CO HR 39。. R O H + R 39。 C H OHgem diol Codeine（ 可待因 ） C H 3NOC H3 O O HC H 3NOH OO HPhenacetin(非那西汀 ) C 2 H 5 O N H C O C H 3 H O N H C O C H3 a c e t a m i n o p h e n 撲 熱 息 痛Indomethacin （ 吲哚美辛 ） NCC H 3C H 2 C O O HR OOC lR = C H3R = HInfluencing factors to the rate of Odealkylation ? 1. The rate of Odealkylation is a function of chain length, ., increasing chain length reduces the rate of dealkylation. ? 2. Steric factors and ring substituents influence the rate of dealkylation, but are plicated by electronic effects. ? 3. Some drug molecules contain more than one ether group, in which case, usually only one ether is dealkylated. Methoxamine （甲氧明） N H 2C H 3O RO C H 3O HR = C H 3R = HIV. Oxidation of pounds containing sulfur ? A. SDealkylation ? B. Oxidative SDesulfuration ? C. SOxidation 6Methylmercaptopurine (6甲硫嘌呤 ) NN NHNS C H 3NN NHNS C H 2 O HNN NHNS HA. SDealkylation active anticancer drug CYP－ 450 B. Oxidative SDesulfuration C=O P=O P=S C=S Thiopental(硫噴妥 ) H NNHC H 3OXHOX = SX = OSDesulfuration Monooxygenase 殺蟲藥對硫磷 O 2 N PSO C 2 H 5O C 2 H 5O 2 N POO C 2 H 5O C 2 H 5磷 酸 二 乙 硝 苯 酯SDesulfuration Monooxygenase C. SOxidation R － S － R 39。 R － S O － R 39。 R － S O 2 － R 39。F M Oo r C Y P 4 5 0Thioridazine(硫利達(dá)嗪 ) NSNC H3S NSNC H3S C H3OC H3m e s o r i d a z i n e美 索 達(dá) 嗪SOxidation Higher activity 免疫抑制劑 Oxisuran NC H 3SOONC H 3SOOOV. Oxidation of Alcohols ? Alcohol dehydrogenase is an NADspecific enzyme located in the soluble fraction of tissue homogenates(組織勻漿 ). ? It exhibits a broad specificity for alcohols. R C H 2 O H + N A D R C H O + N A D H + H +Metabolisms of Alcohols Most primary alcohols aldehydes other secondary tertiary alcohols Some secondary alcohols conjugation ketones excretion acid Oxidation of ethanol ethanol dehydrogenase a microsomal enzyme system (.) 2/3 In intoxication Ethyl aldehyde 1/3 Oxidation of Methanol Methanol dehydrogenase formaldehyde 1/6 the rate of ethanol catalase（過氧化氫酶） xanthine(黃嘌呤） oxidase Ethanol depresses the rate of methanol oxidation by acting as a petitive substrate for alcohol dehydrogenase, reducing the formation of the toxic metabolite. Mefenamic（ 甲滅酸） C O O HN HRC H 3R = C H 3R = C O O HXanthine oxidase aldehyde oxidase dehydrogenase Oxidation of Aldehydes Endogenous aldehydes Primary alcohols biogenic amines exogenous aldehydes carboxylic acids 2. Reductions ? I. Carbonyl reduction ? II. NO2 reduction ? III. Azo reduction I. Reduction of ketone ? Ketones are stable to further oxidation and consequently yield reduction products as major metabolites. alcohols ketones dehydrogenase Acetohexamide(醋磺己脲 ) H 3 C S O 2 N H C O N H C 6 H 6 cOH 3 C S O 2 N H C O N H C 6 H 6 cH O HS() A. Stereospecific S(+)Methadone（ 美沙酮 ） C C H2CC2H5OCHC H3N ( C H3)2C C H2CC2H5 CHC H 3N ( C H3)2H OHS ( ＋ ) M e t h a d o n e3 S , 6 S α ( ) m e t h a d o lS() Stereospecific Naltrexone（納曲酮） NH OOC H2O HONH OOC H2O HO H h u m a n 6 , β h y d r o x y n a l t r e x o lStereospecific Warfarin（ 華法林 ） O?O HP hOORWarfarin quick B. Stereoselective II. Nitro Reduction ? Nitro pounds are reduced to aromatic primary amines by a nitroreductase, presumably through nitrosoamine and hydroxylamine intermediates. ? These reductases are not solely responsible for the reduction of azo and nitro pounds, probably because of reduction by the bacterial flora(細(xì)菌群落）in the anaerobic（厭氧） environment of the intestine. The mechanism of nitro reduction R N O 2O 2O 2R N O 2 R N OH+RNOHe._. 2 ee.H+ R N H O H R N H 2e2 e2 H+2 H+4Nitroquinoline1oxide (4硝基喹啉 1氧化物 ) NN O2ONN H O HO( c a r c i n o g e n e s i s a n d c e l l t o x i c i t y )H y d r o x y l a m i n e i n t e r m e d i a t eNitrobenzene （硝基苯） N O2 N H O H正 鐵 血 紅 蛋 白 癥m e t h e m o g l o b i nClonazapam（ 氯硝西泮 ） NHNOO 2 N NHNOH 2 NC l C lII