Hum. Hercd. 27: 383-388 (1977)
The Acetylator Polymorphism in four Populations of Afghanistan1 H. W. G o ed d e , G. F l a t z , A. G. R a h im i , S. K a ifie , H. G. B e n k m a n n , G. K riese an d H. D elbrück Institut für Humangenetik der Universität Hamburg, Hamburg; Institut für Genetik der Medizinischen Hochschule Hannover, Hannover; Department of Biochemistry, University of Kabul, and Central Bloodbank of Kabul, Kabul, and Innere Klinik und Poliklinik (Tumorforschung), Essen
Key Words. Acetylator polymorphism • N-acetyltransferase • Population genetics • Afghanistan Abstract. Studies of the acetylator polymorphism in Pushtoons, Tajiks, Hazaras and Usbeks living in Afghanistan revealed a lower frequency of the allele Acs in the last two populations. The results were compared with those of other populations. The importance of this polymorphism for therapy and a possible relation to the use of alkaloids in form of spices and drugs is discussed.
Introduction
1 Supported by the ‘Stiftung Volkswagenwerk’, Hannover, FRG.
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/16/2019 2:09:38 AM
The excretion of many natural substances and drugs is dependent on solubilization by esterification with various biological intermediates, e.g., glucuronic acid, acetic acid, sulfuric acid. Several important drugs, such as sulfonamides, isonicotinic acid hydrazide and others are acetylated by an enzyme present in hepatic cells, N-acetyltransferase. A genetically determined polymorphism of this enzyme exists in all human populations so far examined [M o u r a n t et al., 1976] as well as in several other mammalian species, such as monkeys [G of.d d e et al., 1964, 1968], rabbits, rats (W eber et al., 1968], and others. Two groups can be distinguished by studyingthe excretion (acetylation) of an administered dose of a test substance like INH or sulfamethazine. ‘Rapid acetylators’ excrete the drug fast; they correspond to the genotypes homozy gous for the rapid acetylator gene (AcR/AcR) and the heterozygotes (AcR/Acs), whereas the ‘slow acetylators’ are homozygous for the slow acetylator allele (Acs/Acs).
384
G oeddf./F latz/R ahimi/K aifie/B enkmann/K riese/D elbruck
It has been shown that the isoniazid acetylator phenotype is congruent with the acetylator phenotype of several structurally unrelated drugs, such as sulfamethazine [E van s , 1969], sulfapyridine [S chroeder and E vans , 1972], and, presumably with serotonin [G oedde et al., 1968] and dapsone [P eters and L evy ], So far, the population of Afghanistan has not been examined with respect to acetylator phenotypes. Such studies are not only of theoretical and anthro pological interest but also of importance for the practice of medicine. In fast acetylators higher dosages of many drugs are necessary in order to achieve an optimal therapeutic response. On the other hand, the danger of drug toxity (side effects, drug interaction) seems to be greater in slow acetylators due to the slower excretion and correspondingly higher blood levels. In this study four population groups of Afghanistan have been chosen for an acetylation test to estimate the gene frequencies of acetylator phenotypes. The Pushtoons belong to the major population of Afghanistan (about 50%). They are of Indoeuropean origin. Their main settlement areas are in the south and the east of the country. In the very few anthropological studies available they are described as tall, slim, and mesocephalic. The Tajiks (about 25% of the whole population) are known as the oldest ethnic group of Afghanistan and arc the descendants of the previous Iranic population in South Asia. Mostly they are smaller than the Pushtoons, broad faced and brachycephalic. During the 14th century the Hazaras entered the country, they descend probably from Mongols. Hazaras are small with broad heads, high cheek-bones and slant eyes. Mainly they live in the mountainous area of central Afghanistan in poor circumstances. The Usbeks. including some Turkmen, belong to the Turk people. They penetrated the country during the Middle Ages from West-Turkistan and live in the north of Afghanistan. Some mongolid characteristics can be observed.
Individuals of these four Afghan populations have been investigated regar ding the erythrocyte enzyme polymorphisms of EsD, GPT, AcP, PGMj, ADA, AK and 6-PGD [G oedde et al., 1977) and the serum protein polymor phisms C3, Tf, Hp, Gc, Che, axat, Bg and Cp [R ahim i et al., 1977] as well as serum levels of C3, C4, C3 proactivator and the immunoglobulins IgG, IgA and IgM [A g a r w a l et al., 1976], Within this field research also lactose tolerance in Afghanistan has been studied [R ahimi et al., 1976].
Blood samples from 85 Pushtoons, 112 Tajiks, 120 Hazaras and 118 Usbeks were tested.
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Subjects and Methods
385
Acetylator Polymorphism in Afghanistan
Table /. Distribution of acetylators in 4 populations of Afghanistan Population
n
AcRAcR
Pushtoons Tajiks Hazaras Usbeks
85 112 120 119
3 5 15 28
AcRAcs
/o
3.5 4.5 12.5 23.7
25 38 55 59
O /o
29.4 33.9 45.8 50.0
AcsAcs %
AcR
AcS
57 69 50 31
0.1812 0.2152 0.3546 0.4875
0.8188 0.7848 0.6454 0.5125
67.1 61.6 41.7 26.3
For determination of rapid and slow acetylators we applicated sulfamethazine (sulfadi midine) according to E vans [1969] instead of INH (isonicotinic acid hydrazide) in an oral dose of 10 mg/kg body weight to the fasting probands. Venous blood was taken with Manovettes (Sarstedt 950 R, Nümbrecht, FRG) containing 1-1,5 mg/1 EDTA. Two hours after administration, 5 x 0.1 ml of each sample was dropped within small circles on filter paper. After air-drying the prepared papers were sent by air mail to Hamburg and were stored at 4°C before testing. The assay of sulfamethazine and acetylated sulfamethazine was carried out according to W eber and Brenner [1974] (sec also Hoo et al. [1976]) based on methods described by E vans [1969] and Bratton and M arshall [1939]. The free and acetylated sulfamethazine could be dissolved again by addition of trichloracetic acid. The solution was then divided into two parts, one was treated further with 4 n HC1 and boiled, the other was kept untreated at room temperature. The boiling in acid solution caused the deacetylation of acetylated sulfamethazine. The total and free sulfamethazine of both solutions were estimated by diazotization.
Table I demonstrates phenotypes and gene frequencies of the acetylator polymorphism in the four Afghan populations. A distinct separation of rapid and intermediate inactivators was not possible with the method used in this material, so the number of intermediate and rapid acetylators of each group was calculated. Corresponding to the different ethnic background of the four populations studied, gene frequencies of Acs in Pushtoons and Tajiks are similar, whilst in Hazaras and Usbeks lower frequencies were observed. The results of the former two populations are in accordance with values found mainly in Europe, Africa and India. Considerably lower frequencies of Acs are found in certain Mongolid populations (e.g., Taiwan Chinese, 0.41; Japa nese, 0.34; Eskimo, 0.22). According to their gene frequencies the Usbeks and the Hazaras seem to be grouped between Caucasoids and Mongolids. There have been many discussions regarding a possible natural selection leading to such an enzyme polymorphism with different gene frequencies in
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/16/2019 2:09:38 AM
Results and Discussion
G oedde/F latz/R ahimi/K aifie/B enkmann/K riese/D elbrück
various populations. Often a polymorphism is detected using substances like isonicotinic acid hydrazide or suxamethonium (cholinesterase polymor phism), industrial products or drugs, to which previously no exposition could have occurred. Regarding the N-acetyltransferase polymorphism it could be shown [G oeddf ., 1968] that also the physiological substance serotonin is a substrate for the enzyme. Its acetylation - leading to the hormone melatonin - is inhibited by several alkaloids and important psychotropic drugs as well as the acetylation of INH. For instance the alkaloids harmine and rescrpine, the LSD-derivative methysergid (a serotonin antagonist), the antidepressive drugs imipramine and opipramol as well as phenelzine are strong inhibitors. Especially a high affinity of harmine to N-acetyltransferase in a competitive inhibition reaction could be shown. Harmine and some of the psychotropic drugs mentioned are structurally similar to N-acetyiserotonin and to the hor mone melatonin which is 6-methoxyharmala. Harmine occurs in the seeds of Peganum harmala (together with harmaline and harmol) and has been used as a spice and for other purposes in the Middle East for a long time; it is said to have its origin in Turkestan [N a ra n jo , 1967], In Afghanistan 19% of 173 drugs used as spices or intoxicants are alkaloids (including harmine) which are the ingredients of fruits, seed, herbs, blossoms, roots and amorphous drugs [Vo l k , 1955]. For instance also the alkaloid content in cannabis (Haschisch) is very different in various geographical regions. Since the distribution of those alkaloids in different countries and the inci dence of their usage in various populations are very difficult to elucidate nowadays, a possible role of such spices or hallucinogens in selective proces ses leading to the observed increasing frequencies of the ‘slow alleles’ of the N-acetyltransferase polymorphism from the east to the west [M o u r a n t et al., 1976] can only be discussed. The polymorphism of N-acetyltransferase and the knowledge of the gene frequencies in different populations is of interest for the treatment with cer tain drugs. Normally, the individual differences regarding the inactivation of INH have no therapeutic consequence. However, in prolonged isoniazid therapy cumulative interaction reactions and side effects (peripheral neuro pathy) [D ev a datta et a i, 1960] have been observed more frequently in patients who are ‘slow acetylators’. This genetic polymorphism modifies the toxicity and controls the metabolism of different other drugs. Intoxication reactions after hydralazine [P erry et al., 1967] sulfamethazine, phenelzine, sulfasalazine and others have been reported. These and other compounds are subject to metabolic acetylation which corresponds exactly to the acetylation
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/16/2019 2:09:38 AM
386
Acetylator Polymorphism in Afghanistan
.187
of isoniazide. Investigations by P eters and L evy [1971] have shown that the N-acetyltransferase polymorphism is also of interest to the treatment of leprosy. Dapsone seems also to be acetylated in a polymorphic way.
A ckno wledgmen t We are grateful to Mrs. M onika P eters, Apotheke an der Friedenseiche, Hamburg, for helpful technical indications and thank Mr. D jabadchel, Central Bloodbank of Kabul, for his help in collecting the blood samples.
References
globulins, C3, C4 components of complement and C3 proactivator in four different populations of Afghanistan. Hum. Genet. 33: 67 (1976). Bratton, A.C. and M arshall, E.K., jr.: A new coupling component of sulfanilamide determination. J. biol. Chem. 123: 537 (1939). D evaoatta, S.; G angadharam, P. R.: A ndrews, R.H.; Fox, W.; R amakrishan, C.V.; S elkon, J.B., and V elu, S.: Peripheral neuritis due to isoniazid. Bull. Wld Hlth Org. 23 : 587 (1960). E vans, D .A .F.: An improved and simplified method of detecting the acetylator pheno type. J. med. Genet. 6: 405 (1969). G oedde, H.W .; A ltland, K., and Schloot, W.: Therapy of prolonged apnea after suxamethonium with purified pseudocholinesterase. New data on kinetics of the hydrolysis of succinyldicholine and succinylmonocholine and further data on N-acetyltransferase polymorphism. Ann. N. Y. Acad. Sei. 151: 742 (1968). G oedde, H .W .; F latz, G.: R ahimi, A .G .; K aifie, S.: D elbrück, H., and Benkmann, H.G.: Red cell enzyme polymorphisms in different populations of Afghanistan. Ann. Hum. Biol, (in press, 1977). G oedde, H.W .; Schöpf , E., and F leischmann, D.: Studies on pharmacogenetics. 1. The enzymatic acetylation of isonicotinic acid hydrazidc (INH). Biochem. Pharmacol. 13: 1671 (1964). Hoo, J.J.; H ussein, L., and G oedde, H .W .: A simplified micromcthod for the determin ation of the acetylator phenotype. Z. klin. Chem. klin. Biochem. (in press, 1977). M ourant , A. E.; K ope?, A.C., and D omaniewska-Sobczak, K.: The distribution of human blood groups and other polymorphisms (Oxford University Press, London 1976). N aranjo, D.: Psychotropic properties o f the harmala alkaloids; in E fron Ethnopharmacologic search for psychoactive drugs. U.S. Public Health Serv. Up. Nor. 1645, Washington (1967). P erry, H .M .; S akamoto, A., and T an , E.M.; Relationship of acetylating enzyme to hydralazine toxicity. Proc. Cent. Soc. Clin. Res. 40: 81 (1967).
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/16/2019 2:09:38 AM
Agarwal , D .P.; G oedde, H.W.; Benkmann, H .G .: F latz, G.: R ahimi, A .G .; K aifie, S., and D elbrück, H.: Genetic polymorphisms of C3 and serum levels of immuno
388
G oedde/F latz/R ahimi/K aifie/B enkmann/K riese/D elbrück
P eters, J. H. and L evy, L .: Dapsone acetylation in man. Another example of polymorphic
acetylation. N. Y. Acad. Sei. 179: 660 (1971). R ahimi, A .G .; G oedde, H.W .; F latz, G.; K aifie, S.; Benkmann, H.G., and D el brück , H.: Serum protein polymorphisms in different populations of Afghanistan
Am. J. Hum. Genet, (in press, 1977) R ahimi, A.G.; D elbrück, H.; H eckl, R.: G oedde, H.W., and F latz , G.: Persistence o f
Prof. Dr. H. W. G oedde, Institut für Humangenetik der Universität Hamburg, Butenfeld Nr. 32, D-2 Hamburg 54 (FRG)
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/16/2019 2:09:38 AM
high intestinal lactase activity (lactose tolerance) in Afghanistan. Hum. Genet. 34: 57-62 (1976). Schroeder, H. and E vans, D .A .P.: The polymorphic acetylation of sulphapyridine in man. J. med. Genet. 9: 168 (1972). Volk , O .H .: Afghanische Drogen. Planta med. 3: 129 (1955). W eber, W.W. and Brenner, W.: A filter paper method for determining isoniazid acetylator phenotype. Am. J. hum. Genet. 26 : 467 (1974). W eber, W. W.; C ohen, S. N., and Steinberg, M. S.: Purification and properties of Nacetyltransferase from mammalian liver. Ann. N. Y. Acad. Sei. 151: 734 (1968).
The Acetylator Polymorphism in four Populations of Afghanistan1 H. W. G o ed d e , G. F l a t z , A. G. R a h im i , S. K a ifie , H. G. B e n k m a n n , G. K riese an d H. D elbrück Institut für Humangenetik der Universität Hamburg, Hamburg; Institut für Genetik der Medizinischen Hochschule Hannover, Hannover; Department of Biochemistry, University of Kabul, and Central Bloodbank of Kabul, Kabul, and Innere Klinik und Poliklinik (Tumorforschung), Essen
Key Words. Acetylator polymorphism • N-acetyltransferase • Population genetics • Afghanistan Abstract. Studies of the acetylator polymorphism in Pushtoons, Tajiks, Hazaras and Usbeks living in Afghanistan revealed a lower frequency of the allele Acs in the last two populations. The results were compared with those of other populations. The importance of this polymorphism for therapy and a possible relation to the use of alkaloids in form of spices and drugs is discussed.
Introduction
1 Supported by the ‘Stiftung Volkswagenwerk’, Hannover, FRG.
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/16/2019 2:09:38 AM
The excretion of many natural substances and drugs is dependent on solubilization by esterification with various biological intermediates, e.g., glucuronic acid, acetic acid, sulfuric acid. Several important drugs, such as sulfonamides, isonicotinic acid hydrazide and others are acetylated by an enzyme present in hepatic cells, N-acetyltransferase. A genetically determined polymorphism of this enzyme exists in all human populations so far examined [M o u r a n t et al., 1976] as well as in several other mammalian species, such as monkeys [G of.d d e et al., 1964, 1968], rabbits, rats (W eber et al., 1968], and others. Two groups can be distinguished by studyingthe excretion (acetylation) of an administered dose of a test substance like INH or sulfamethazine. ‘Rapid acetylators’ excrete the drug fast; they correspond to the genotypes homozy gous for the rapid acetylator gene (AcR/AcR) and the heterozygotes (AcR/Acs), whereas the ‘slow acetylators’ are homozygous for the slow acetylator allele (Acs/Acs).
384
G oeddf./F latz/R ahimi/K aifie/B enkmann/K riese/D elbruck
It has been shown that the isoniazid acetylator phenotype is congruent with the acetylator phenotype of several structurally unrelated drugs, such as sulfamethazine [E van s , 1969], sulfapyridine [S chroeder and E vans , 1972], and, presumably with serotonin [G oedde et al., 1968] and dapsone [P eters and L evy ], So far, the population of Afghanistan has not been examined with respect to acetylator phenotypes. Such studies are not only of theoretical and anthro pological interest but also of importance for the practice of medicine. In fast acetylators higher dosages of many drugs are necessary in order to achieve an optimal therapeutic response. On the other hand, the danger of drug toxity (side effects, drug interaction) seems to be greater in slow acetylators due to the slower excretion and correspondingly higher blood levels. In this study four population groups of Afghanistan have been chosen for an acetylation test to estimate the gene frequencies of acetylator phenotypes. The Pushtoons belong to the major population of Afghanistan (about 50%). They are of Indoeuropean origin. Their main settlement areas are in the south and the east of the country. In the very few anthropological studies available they are described as tall, slim, and mesocephalic. The Tajiks (about 25% of the whole population) are known as the oldest ethnic group of Afghanistan and arc the descendants of the previous Iranic population in South Asia. Mostly they are smaller than the Pushtoons, broad faced and brachycephalic. During the 14th century the Hazaras entered the country, they descend probably from Mongols. Hazaras are small with broad heads, high cheek-bones and slant eyes. Mainly they live in the mountainous area of central Afghanistan in poor circumstances. The Usbeks. including some Turkmen, belong to the Turk people. They penetrated the country during the Middle Ages from West-Turkistan and live in the north of Afghanistan. Some mongolid characteristics can be observed.
Individuals of these four Afghan populations have been investigated regar ding the erythrocyte enzyme polymorphisms of EsD, GPT, AcP, PGMj, ADA, AK and 6-PGD [G oedde et al., 1977) and the serum protein polymor phisms C3, Tf, Hp, Gc, Che, axat, Bg and Cp [R ahim i et al., 1977] as well as serum levels of C3, C4, C3 proactivator and the immunoglobulins IgG, IgA and IgM [A g a r w a l et al., 1976], Within this field research also lactose tolerance in Afghanistan has been studied [R ahimi et al., 1976].
Blood samples from 85 Pushtoons, 112 Tajiks, 120 Hazaras and 118 Usbeks were tested.
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/16/2019 2:09:38 AM
Subjects and Methods
385
Acetylator Polymorphism in Afghanistan
Table /. Distribution of acetylators in 4 populations of Afghanistan Population
n
AcRAcR
Pushtoons Tajiks Hazaras Usbeks
85 112 120 119
3 5 15 28
AcRAcs
/o
3.5 4.5 12.5 23.7
25 38 55 59
O /o
29.4 33.9 45.8 50.0
AcsAcs %
AcR
AcS
57 69 50 31
0.1812 0.2152 0.3546 0.4875
0.8188 0.7848 0.6454 0.5125
67.1 61.6 41.7 26.3
For determination of rapid and slow acetylators we applicated sulfamethazine (sulfadi midine) according to E vans [1969] instead of INH (isonicotinic acid hydrazide) in an oral dose of 10 mg/kg body weight to the fasting probands. Venous blood was taken with Manovettes (Sarstedt 950 R, Nümbrecht, FRG) containing 1-1,5 mg/1 EDTA. Two hours after administration, 5 x 0.1 ml of each sample was dropped within small circles on filter paper. After air-drying the prepared papers were sent by air mail to Hamburg and were stored at 4°C before testing. The assay of sulfamethazine and acetylated sulfamethazine was carried out according to W eber and Brenner [1974] (sec also Hoo et al. [1976]) based on methods described by E vans [1969] and Bratton and M arshall [1939]. The free and acetylated sulfamethazine could be dissolved again by addition of trichloracetic acid. The solution was then divided into two parts, one was treated further with 4 n HC1 and boiled, the other was kept untreated at room temperature. The boiling in acid solution caused the deacetylation of acetylated sulfamethazine. The total and free sulfamethazine of both solutions were estimated by diazotization.
Table I demonstrates phenotypes and gene frequencies of the acetylator polymorphism in the four Afghan populations. A distinct separation of rapid and intermediate inactivators was not possible with the method used in this material, so the number of intermediate and rapid acetylators of each group was calculated. Corresponding to the different ethnic background of the four populations studied, gene frequencies of Acs in Pushtoons and Tajiks are similar, whilst in Hazaras and Usbeks lower frequencies were observed. The results of the former two populations are in accordance with values found mainly in Europe, Africa and India. Considerably lower frequencies of Acs are found in certain Mongolid populations (e.g., Taiwan Chinese, 0.41; Japa nese, 0.34; Eskimo, 0.22). According to their gene frequencies the Usbeks and the Hazaras seem to be grouped between Caucasoids and Mongolids. There have been many discussions regarding a possible natural selection leading to such an enzyme polymorphism with different gene frequencies in
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/16/2019 2:09:38 AM
Results and Discussion
G oedde/F latz/R ahimi/K aifie/B enkmann/K riese/D elbrück
various populations. Often a polymorphism is detected using substances like isonicotinic acid hydrazide or suxamethonium (cholinesterase polymor phism), industrial products or drugs, to which previously no exposition could have occurred. Regarding the N-acetyltransferase polymorphism it could be shown [G oeddf ., 1968] that also the physiological substance serotonin is a substrate for the enzyme. Its acetylation - leading to the hormone melatonin - is inhibited by several alkaloids and important psychotropic drugs as well as the acetylation of INH. For instance the alkaloids harmine and rescrpine, the LSD-derivative methysergid (a serotonin antagonist), the antidepressive drugs imipramine and opipramol as well as phenelzine are strong inhibitors. Especially a high affinity of harmine to N-acetyltransferase in a competitive inhibition reaction could be shown. Harmine and some of the psychotropic drugs mentioned are structurally similar to N-acetyiserotonin and to the hor mone melatonin which is 6-methoxyharmala. Harmine occurs in the seeds of Peganum harmala (together with harmaline and harmol) and has been used as a spice and for other purposes in the Middle East for a long time; it is said to have its origin in Turkestan [N a ra n jo , 1967], In Afghanistan 19% of 173 drugs used as spices or intoxicants are alkaloids (including harmine) which are the ingredients of fruits, seed, herbs, blossoms, roots and amorphous drugs [Vo l k , 1955]. For instance also the alkaloid content in cannabis (Haschisch) is very different in various geographical regions. Since the distribution of those alkaloids in different countries and the inci dence of their usage in various populations are very difficult to elucidate nowadays, a possible role of such spices or hallucinogens in selective proces ses leading to the observed increasing frequencies of the ‘slow alleles’ of the N-acetyltransferase polymorphism from the east to the west [M o u r a n t et al., 1976] can only be discussed. The polymorphism of N-acetyltransferase and the knowledge of the gene frequencies in different populations is of interest for the treatment with cer tain drugs. Normally, the individual differences regarding the inactivation of INH have no therapeutic consequence. However, in prolonged isoniazid therapy cumulative interaction reactions and side effects (peripheral neuro pathy) [D ev a datta et a i, 1960] have been observed more frequently in patients who are ‘slow acetylators’. This genetic polymorphism modifies the toxicity and controls the metabolism of different other drugs. Intoxication reactions after hydralazine [P erry et al., 1967] sulfamethazine, phenelzine, sulfasalazine and others have been reported. These and other compounds are subject to metabolic acetylation which corresponds exactly to the acetylation
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/16/2019 2:09:38 AM
386
Acetylator Polymorphism in Afghanistan
.187
of isoniazide. Investigations by P eters and L evy [1971] have shown that the N-acetyltransferase polymorphism is also of interest to the treatment of leprosy. Dapsone seems also to be acetylated in a polymorphic way.
A ckno wledgmen t We are grateful to Mrs. M onika P eters, Apotheke an der Friedenseiche, Hamburg, for helpful technical indications and thank Mr. D jabadchel, Central Bloodbank of Kabul, for his help in collecting the blood samples.
References
globulins, C3, C4 components of complement and C3 proactivator in four different populations of Afghanistan. Hum. Genet. 33: 67 (1976). Bratton, A.C. and M arshall, E.K., jr.: A new coupling component of sulfanilamide determination. J. biol. Chem. 123: 537 (1939). D evaoatta, S.; G angadharam, P. R.: A ndrews, R.H.; Fox, W.; R amakrishan, C.V.; S elkon, J.B., and V elu, S.: Peripheral neuritis due to isoniazid. Bull. Wld Hlth Org. 23 : 587 (1960). E vans, D .A .F.: An improved and simplified method of detecting the acetylator pheno type. J. med. Genet. 6: 405 (1969). G oedde, H.W .; A ltland, K., and Schloot, W.: Therapy of prolonged apnea after suxamethonium with purified pseudocholinesterase. New data on kinetics of the hydrolysis of succinyldicholine and succinylmonocholine and further data on N-acetyltransferase polymorphism. Ann. N. Y. Acad. Sei. 151: 742 (1968). G oedde, H .W .; F latz, G.: R ahimi, A .G .; K aifie, S.: D elbrück, H., and Benkmann, H.G.: Red cell enzyme polymorphisms in different populations of Afghanistan. Ann. Hum. Biol, (in press, 1977). G oedde, H.W .; Schöpf , E., and F leischmann, D.: Studies on pharmacogenetics. 1. The enzymatic acetylation of isonicotinic acid hydrazidc (INH). Biochem. Pharmacol. 13: 1671 (1964). Hoo, J.J.; H ussein, L., and G oedde, H .W .: A simplified micromcthod for the determin ation of the acetylator phenotype. Z. klin. Chem. klin. Biochem. (in press, 1977). M ourant , A. E.; K ope?, A.C., and D omaniewska-Sobczak, K.: The distribution of human blood groups and other polymorphisms (Oxford University Press, London 1976). N aranjo, D.: Psychotropic properties o f the harmala alkaloids; in E fron Ethnopharmacologic search for psychoactive drugs. U.S. Public Health Serv. Up. Nor. 1645, Washington (1967). P erry, H .M .; S akamoto, A., and T an , E.M.; Relationship of acetylating enzyme to hydralazine toxicity. Proc. Cent. Soc. Clin. Res. 40: 81 (1967).
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/16/2019 2:09:38 AM
Agarwal , D .P.; G oedde, H.W.; Benkmann, H .G .: F latz, G.: R ahimi, A .G .; K aifie, S., and D elbrück, H.: Genetic polymorphisms of C3 and serum levels of immuno
388
G oedde/F latz/R ahimi/K aifie/B enkmann/K riese/D elbrück
P eters, J. H. and L evy, L .: Dapsone acetylation in man. Another example of polymorphic
acetylation. N. Y. Acad. Sei. 179: 660 (1971). R ahimi, A .G .; G oedde, H.W .; F latz, G.; K aifie, S.; Benkmann, H.G., and D el brück , H.: Serum protein polymorphisms in different populations of Afghanistan
Am. J. Hum. Genet, (in press, 1977) R ahimi, A.G.; D elbrück, H.; H eckl, R.: G oedde, H.W., and F latz , G.: Persistence o f
Prof. Dr. H. W. G oedde, Institut für Humangenetik der Universität Hamburg, Butenfeld Nr. 32, D-2 Hamburg 54 (FRG)
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/16/2019 2:09:38 AM
high intestinal lactase activity (lactose tolerance) in Afghanistan. Hum. Genet. 34: 57-62 (1976). Schroeder, H. and E vans, D .A .P.: The polymorphic acetylation of sulphapyridine in man. J. med. Genet. 9: 168 (1972). Volk , O .H .: Afghanische Drogen. Planta med. 3: 129 (1955). W eber, W.W. and Brenner, W.: A filter paper method for determining isoniazid acetylator phenotype. Am. J. hum. Genet. 26 : 467 (1974). W eber, W. W.; C ohen, S. N., and Steinberg, M. S.: Purification and properties of Nacetyltransferase from mammalian liver. Ann. N. Y. Acad. Sei. 151: 734 (1968).
