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CTR f f 1 f 011057

JEFFREY ROBERT IDLE CURRICULUM VITAE July 1986 1 ~ EXHIBIT ~ _, J 1 !.r fR E 46''l ti..4 k1OSQc

BIOGRAPHY Name: Jeffrev Robert Idle Date of birth: 17 September, 1950 Marital status: Divorced Children: One daughter, aged S Business address: ^ Department of Pharmacology St Mary's Hospital Medical School Norfolk Place Paddington LONDON S:2 IPG ENGLAND telephone 01-723-1252 (ext. 146,1 Home address: EDL'CATION 4 Nicol Close St Margarets Twickenham Middlesex T'V1 1RP ENGLAND telephone 01-891-3968 Educated at Kendal Grammar School, 1961-1968; The Hatfie: Polytechnic, 1968-1973; University of London (St. Mary's Hospita: Medical School), 1973-1976. 7 7 - -.:. J: ........ 1972 B.Sc. in Applied Cheristry 1973 B.Sc.(First Class Hons.) in Medicinal Chemis*_r•: 1973 Graduate of the Royal Institute of Chemis. 19%6 Ph.D. in Biochemistr•, APPOI: ."4r,NTS 1971 Research Assistant. Ciba-Geigy Limited 1972 Research Chemist, ~ander Limited 1976 Lecturer in Biochemistry, St. Mar;'s Hospital Medical Sc^ce: 1976 Lecturer in Biochemical Pharmacolog-:, St. Marv's Hospita: Medical School 198: .:ellcome Trust Senior Lecturer, St. `:a-•:'s Hosnital School 19c5' Reader in Pharmacogenetics, liniversi _ o; i.ondon =-<< 6_50 L.r t {w•, L i N k.+* .L. 10EEt Si

EXTERNAL COMMITTEES AND BOARDS 1984 Lung Cancer Task Force, NCI, NIH, USA 1986 Cancer Research Advancement Board, Irish Cancer Soc:e=•: Dublin, Eire 1986 Scientific Advisory Board, The Council for Tobacco Research, USA, Inc., New York, USA INTERNAL COMMITTEES AND BOARDS Academic Board [elected preclinical representative, 1982-1988] BSc Committee [Chairman, 1984-presentJ Preclinical Curriculum Committee [ex officio, 1984-present; Safety Committee [Advisor on Chemical Carcinogens, 1986; Smoking and Health Working Party (Chairman, 1985-present] Various other ad hoc committees and working parties c-. institutional, educational and research matters. TEACHING EXPERIENCE The candidate has been a practical class demonstrator since '_9-?. lectured Part I M.B.,B.S. Biochemistry, Part III ": B L; Pharmacology, B.Sc. Pharmacology intercalated units and =`:e University inter-collegiate Biochemistry course at St. Mary's. ::e is an Appointed Teacher and Examiner for Part III M.B.,B.S. ar.c has personally supervised eleven Ph.D. and M.D. students. He has also acted as a Ph.D. examiner. The candidate has been acti•:e'.•: involved in the gradual modernisation and restructuring of the Part III course at St.Harv's since 1976 and has developed a number of nev student practicals with an emphasis of observa::o-. of drug effects in man and their variability. He continues .. 3 C= -i, _ 6 _..1 Cl'- i iN 0.4 10GO

supervise several Clinical Course Project students, one of %:i:o7n, Hilary Devonshire was awarded the Max Bohn Medal for her work on phenacetin metabolism and toxicity. Two of his other studen=s (Kim Lumley and Mark Cooper) were awarded prizes. RESEARCH TRAINING AND ACTIVITIES The candidate trained in drug metabolism with the late Professor R.T. Williams at which time he became involved in the problems of variability in the processes of biotransformation of drugs ar._~ toxic chemicals through studies of inter-species variatior.. Transferring to the then new Department of Biochemical and Experimental Pharmacology in 1976 on a Wellcome Trust-supported lectureship, and being fortunate to work in collaboration w:t`: Dr. Richard Lancaster and Professor R.L. Smith, he was involved in following up the observation of a single human volunteer who had responded adversely to a single dose of the hypotensive drug debrisoquine. He developed a simple, rapid and reproducible assa:: for debrisoquine and its major urinary metabolite, which was t.._ overture to the organisation and execution of the first population and familv study of its kind, screening subiects for their ability to hydroxylate debrisoquine, identifying others with the same apparer.t defect of metabolism as the firs: uncovered by Dr. Lancaster and investigation of their c:ose relatives. From these investigations was born the first example of genetic polymorphism, in human drug metabolic oxidat'_ern recounted in the Lancet in 1977. 4 C TR NN 01 1061

From this point a number of urgent investigations were perceived. In order to achieve these, it was necessary to bring ne_ personnel with specialised abilities into the laboratory and develop collaboration with various experts outside. At present, a research group of some 12 scientists has been assembled •:it:i- the department, representing skills in biochemistry, pharmacology, pharmacy, drug metabolism, analytical chemist_::. pharmacokinetics, statistics, cardiovascular and chest medicine. This has in part been made possible by the award of researc:-n grants from The Wellcome Trustees, The Cancer Research Campaiz::. National Cancer Institute (USA) and the drug industry underpin the continuity of the current programme. The rai-: aspects of the polymorphism which have been persued by t^e candidate and his research group include inter-ethnic variatio-. in allele frequency, definition of the scope of the polymorphis= with respect to the metabolism of other drugs, effect of phenotype on the pharmacokinetics of, and response tc. polymorphically oxidised drugs, contribution of phenotype to t::e aetiologv of adverse drug reactions, the contribution phenotype to the outcome of cancer chemotherapy and adverse responses to anti-cancer drugs and to the aetiology of certa:-n carcinomas associated with the metabolic activation o: environmental procarcinogens, such as the polycyclic aromatic hydrocarbons and the nitrosamines in cigarette smoke and t~:e mycotoxins. Two of the more recent developments have been first'_•: the finding that the polymorphism occurs in rats and thus opportunity now exists to investigate toxicological sequelae 5 ! , 1 R t l 1 "! 011OG2_-

the variant allele without recourse to human studies, finding that the homozygous recessive rats wit'.^h defic?en : oxidation are hypercholestraemic, apparently due in part to ara effect upon bile acid synthesis from cholesterol. This observation may lead.to a better understanding of the diathes'_s Secondly, we have introduced the use of pharmacogenetic measurements in the biochemical epidemiology of cancer. 7he findings of a study of bronchogenic carcinoma and smoking cont:o: patients have recently been reported in Nature (vide infra) and may herald a long-overdue change in the practice of epidemioloc::. Collaboration has been established with the Laboratory of Hu.-a-. Carcinogenesis and the Epidemiology Branch, National Cancer Institute, NIH to develop a biochemical epidemiological approac` to lung cancer risk and thus to persue the host factors whic:: determine individual lung cancer risk. Finally, a principal responsibility of the candidate's laboratory is to uncover and characterize new genetic polymorphisms c: metabolic oxidation. This systematic approach is the d:i•:ir._ force behind pharmacocenetics, revealing new phenomena whic^ ca-n be evaluated at the ger,etic, toxicological and clinical level. :.n accord with this philosophy, we have broadened the perspective investigating oxidative processes which do not necessa_'_::• involve carbon atoms or indeed cytochrome P-450. We are now seeing emerge quite clearly genetic polymorphisms of sulphur anc nitrogen oxidation, together with dehydrogenation reactions. Clearly, the processes of metabolic oxidation are more genetically variable t:an was hither to suspected and the nu.:.be: of candidate compounds for these processes is thus considerabie 6 _ _ _ _ lo b - 5 y CTR HN 01 10631

The implications of the foregoing to public health are now :ess nebulous. Since polymorphic enzymes are the interface between rar, and his environment, chemically-induced disease must have a significant genetic component. In summary, the question being addressed by the researc: programme is what is the impact of these human genes on man's interaction with his chemical environment? The potential now exists to take major steps forward in understanding the causes of many iatrogenic diseases and certain natural ones and, hopefullv, how to prevent or restrict their occurrence. In the future, this will require even greater links with our clinical colleagues within and without St. Mary's, abroad and with the drug industry. The subject of pharmacogenetics is now no longer an academic curiosity but a vibrant, active and developing field which is questioning the origins of man's individuality in his response to the chemical provocations of the modern environment. 7 CTR HN 011064

PUBLICATIONS 1974 Bridges JW, Evans ME, Idle JR, Miliburn P, Osiyemi F"v, Smith :, . Williams RT.• The conjugation of indolylacetic acid in man, monkeys and other species. Xenobiotica 1974;4:645-652. 1975 Caldwell J, French MR. Idle JR, Renwick AG, Bassir 0, Williams RT Conjugation of foreign compounds in the elephant and hyaena. FEBS Lett 1975;60:391-395. Idle JR, Millburn P, Williams RT. Benzoylglutan:ic acid, a metabolite of benzoic acid in Indian fruit bats. FEBS Let: 1975;59:234-236. 1976 Idle JR, Millburn P, Williams RT. Taurine conjugation of arylacetic acids in the ferret. Biochem Soc Tra-s 1976;4:139-141. Idle JR. Millburn P. Williams RT, Zini G. The conjugatiorn c: arylacetic acids in the pigeon compared to the hen. Bioc:^.e- Soc Trans 1976;µ:1-"1-143. Angelo YM, Dring LG, idle JR, Lancaster R, Mahgoub A, Smi th ..L. Defective alicyclic hydroxylation of debrisoquine in man. J C?in Pharmaco'_ i977;4:725P. 8 V' TRi i N 0110615

Angelo MM, Idle JR. The conjugation of benzoic acid anc phenylacetic acid by the Pipestrelle bat. Co-.o Eiec::e- Phvsiol 1977;58C:57-59. Collins-MW, French MR, Hirom PC, Idle JR, Bassir 0, Williams RT. The conjugation of benzoic.acid in the African bat Epomc~s franqueti Comv Biochem Physiol 1977;56C:103-104. Hirom PC, Idle JR, Millburn P. Comparative aspects of t:.e biosynthesis and excretion of xenobiotic conjugates by non- primate mammals. In: DruR Metabolism from Microbe to ua:: (RL Smith and DV Parke, eds) pp.299-329, Taylor & Frar.cis Ltd., London (1977). Hirom PC, Idle JR, Millburn P, Williams RT. Glutamir.e conjugation of phenylacetic acid in the ferret. Biochem Sec Trans 1977;5:1033-1035. Mahgoub A, Idle JR, Dring LC, Lancaster R, Smith RL. :. population and familial study of the defective hvdroxylatiorn of debrisoquine. Br J Clin Pharmacol 1977;4:726P. Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL. Polymorphic hydroxylation of debrisoquine in man. Lancet 1977;ii:5-S-.- 586. 1978 Idle JP., Mahgoub A, Lancaster P., Smith RL. Hypotensive response to debrisoquine and hvdroxylation phenotype. Life Sc: 1978;22:979-984. 0 CTR i i i i 011066

Idle JR, Millburn P, Williams RT. Taurine conjugates as metabolites of arylacetic acids in the ferret. Xenobiot'-c=_ 1978;8:253-264. Idle JR, Sever PS. Collecting it. World Medicine 1978; (Sept. 6). r• Lancaster R, Mahgoub A, Idle J-R, Smith RL. Alic;:c_i: hydroxylation phenotype and the hypotensive response to debrisoquine Proc 7th Internat Congr Pharmacol 1978:2789. Mahgoub A, Idle JR, Smith RL. A population and familial study the defective alicyclic hydroxylation of debrisoquine amo^_ Egyptians. Xenobiotica 1978;9:51-56. Sloan TP, Idle JR, Lancaster R, Smith RL. Alicvc:ic hydroxylation phenotype status and the elimination kinetics of debrisoquine. Proc 7th Internat Con.gr Pharmaco: 1978:2866. Sloan TP, Mahgoub A, Lancaster R, Idle JR, Smith Polymorphism of carbon oxidation of drugs and cl'_nica: implications. Br Med J 1978;2:655-657. Smith RL, Idle JR, Mahgoub A, Sloan TP, Lancaster R. Genetica_'_v determined defects of oxidation at carbon centres of drues. Lancet 1978;i:943-944. 10 CTR_ HN 011067

1979 Andoh B, Idle JR, Mahgoub A, Sloan TP, Smith RL, Woolhouse ":`:. Polymorphic hydroxylation of debrisoquine in Ghanaians. Br _ Pharmacol 1979;66:431P. - Idle JR, Mahgoub A, Angelo MM, Dring LG, Lancaster R, Smith RL. 14 The metabolism of [ Cj-debrisoquine in man. Br J Clin Pharmacol 1979;7:257:266. Idle JR, Ritchie JC, Smith RL. Oxidation phenotype and metiamide metabolism. Br J Pharmacol 1979;66;432P. Idle JR, Sloan TP, Smith RL, Wakile LA. Application of the phenotyped panel approach to the detection of polymorphisW of drug oxidation. Br J Pharmacol 1979;66:430-431P. Idle JR, Smith RL. Polymorphisms of oxidation at carbon centers of drugs and their clinical significance. Dzug Metab Rev 1979;9:301-317. Kitchen I, Trembla; J, Andre J, Dring LG, Idle JR, Sr„1 tl-: P.L, Llilliams P.T. Interindividual and interspecies variation '_.. the metabolism of the hallucinogen 4-methoxy-ampheta;nine. Xenobiotica 1979;9:397-404. Mahgoub A, Idle JR, Smith RL. Geneticallv determined variabilit•~ in drug metabolism: dual slow acet;:lation and drug oxidatiorn traits. Lancet 1979;ii:154. Mutawa M, Islam SI, Idie Jr2. Drug oxidation in phenylketonuria Proc Conference on Paediatric Disease (Kuwait) 1979. 11 V' TR( i i i 01106B

t.:al:ile LA, Sloan TP, Idle JR, Smith RL. Genetic evidence for t.._ involvement of different oxidative mechanisms in d:u: oxidation. J Pharm Pharmacol 1979;31:350-352. ldoolhouse NM,. Andoh B, Mahgoub A, Sloan TP, Idle JR, Smith R:-. Debrisoquine hydroxylation polymorphism among Ghanaians anc caucasians. Clin Pharmacol Ther 1979;26'.584-591. 1980 Andoh B, Idle JR. Sloan TP, Smith RL, Uoolhouse NM. Inter-eth::ic and inter-phenotype differences among Ghanaians anc caucasians in the metabolic hydroxylation of phenytoin. J Clin Pharmacol 1980;9:282-283P. V _ Bababunrni EA, Idle JR, --Mahgoub A, Mbanefo C, Smith RL. Polymorphic hydroxylation of debrisoquine in Nigerians. B: J Clin Pharmacol 1980;9:112-113P. Caldwell J, Idle JR, Smith RL. The amino acid conjugations. :... ExtraheDatic Metabolism of Drur,s and Other Foreitn (TE Gram, ed) pp.453-492, Spectrum Publications, Ne: Yc::: (1980). Chapman PH, Idle JR, Mahgoub A, Mucklow JC, Rawlins MD, Rogers S, Shuster S, Smith RL. 4-Hydroxylation of debrisoquine _- psoriasis. Br J Clin Pharmacol 1980;9:113-114P. Chapman PH, Idle JR, Mahgoub A, Rawlins MD, Smith RL, Shuster S. Drug oxidation in psoriasis. Br J Dermatoi 1980;102:72E. 12 l.r tR F EN 0.! 1OC°9

Danhof M, Breimer D, Sloan TP, Idle JR, Smith RL. Antip,:ri::e metabolite formation in extensive and poor hydroxylators o: debrisoquine. Proc 1st World Conzr Clin Pharmacol (w'emb:ev; 1980. Hetzel MR, Law M, Keai EE, Sloan TP, Idle JR, Smith RL. Is there a genetic component in bronchial carcinoma in smokers' Thorax 1980;35:709. Idle JR. A novel role for taurine. In: Sulphur in Biologv; Ciba Foundation Symposium, No.72, pp.282-284 (1980). Idle JR, Oates NS, Ritchie JC, Shah RR, Sloan TP, Smith RL. Ne_ perspectives of genetic polymorphism in drug metabolisW. Advanced Medicine 1980;16:227-234. Idle JR, Smith RL. Inter-ethnic differences in the metabo'::c disposition of drugs and toxic substances. In: Toxicoloe•: ' the Tropics (RL Smith and EA Bababunmi, eds) pp.239-253. Taylor & Francis Ltd., London (1980). Islam SI, Idle JR. Polymorphic drug oxidation among Saudis. ?:c: 5th Saudi Medical `ieetinQ 1980:101. Islam SI, Idle JR, Smith RL. The polymorphic 4-hydroxvlatio^n o: debrisoquine in a Saudi arab population. Xenobiotica 1980;10:819-825. Mbanefo C, Bababunmi EA, Mahgoub A, Sloan TP, Idle JR, Smith ?.. A study of the debrisoquine hvdroxylation polymorphis:c i.. a Nigerian population. Xenobiotica 1980;10:811-818. 13 ., _ - - - 7 . .. . CTR i i{ i 011070

Mucklow JC, Caraher KT, Idle JR. Rawlins "'J, Sloan TP, Smith R:., Wood P_ The influences of changes of dietary fat on t:e clearance of antipyrine and the 4-hvdroxviation of debrisoquine. Br J Clin Pharmacol 1980;9:283P. Oates NS, Shah RR, Idle JR, Smith RL. On the urinary disposition of phenformin and 4-hydroxy-phenformin 'and their rapid simultaneous measurement. J Pharm Phai-macol 1980;32:7'_:- 732. Price-Evans DA, Mahgoub A, Sloan TP, Idle JR, Smith RL. A fami:_r and population study of the genetic polymorohisT. : debrisoquine oxidation in a British white population. J?le-~ Cenet 1980;17:102-105. Ritchie JC, Sloan TP, Idle JR, Smith RL. Toxicologica: implications of polymorphic drug metabolism. In: Environmental Chemicals, Enzvme Function and Human Ciba Foundation Symposium No 76, pp.219-244 (1980). Disease Shai: F.: , Oates NS, ldle JR, Smi", RL. Genetic i-,pairmer,_ phenformin metabolism. Lancet 1980;i:1147. 1981 Al-Dabbagh SG, Idle JR, Smith RL. Animal modelling of humar. polymorphic drug oxidation - the metabolism of deb:isoc,uine and phenacetin in rat inbred strains. J Pharm Pharmacol :98';33:161-164. 14 C T HN 011. 0'r 1

Danhof M, Idle JR, Teunissen M'wE, Sloan T?, Breimer DD, Smith =_. Influence of the -generically controlled deficiency debrisoquine hydroxylation on antipyrine metabol'_-~ formation. PharmacoloQv.1981;22:349-358. Idle JR. Hydroxylation phenotype and hepatocellular carcinoma. In: Druq Reactions and the Liver (M Davis, JM Treger and ? Williams, eds) pp:313-315, Pitman Medical, London (1981). Idle JR, Islam SI. Polymorphism of phenformin 4-hydroxylation i.. Saudi females. Br-J Pharmacoi 1981;72:177-178P. Idle JR, Mahgoub A, Sloan TP, Smith RL, Mbanefo CO, Bababu=i_-.. Some observations of the oxidative phenotype status cf Nigerian patients presenting with cancer. Cancer Let: 1981;11:331-338. Idle JR, Oates NS, Shah RR, Smith RL. Is there a genet:c predisposition to phenformin induced lactic acidosis? Clin Pharmacol 198':;11:418-419P. idle JR, Osikowska B::, Sever PS, Swinbourne FJ. Pitfalls in synthesis and authentication of dopamine 0-sulphates. Pharmacol 1981; )4: 837p. Islam SI, Idle JR. Increased risk from environmental carcinogens in Saudis. Proc 6th Saudi Medical Meetine, 1981. Mitchell SC, Waring RH, Idle JR. Smith RL. Cimetidine pretreatment decreases carbocvsteine sulphoxidation I,, m.:a;.. I R.C.S. Med Sc: ?9E:;9:1028-1029. 15 C T R t11N 0 11072

Oates NS, Shah RR, Idle JR, Smith RL. Phenformin-induced :act'_c acidosis with impaired debrisoquine hydroxvlatior.. :_a^ce_ 1981;i:837-838. H Sloan TP, Idle JR, Smith RL. Influence of the D/Dy alleies regulating debrisoquine oxidation on pheny:o:-: hydroxylation. Clin Pharmacol Ther 1981;29:493-497. Smith RL, Idle JR. Genetic polymorphism in drug oxidation. In: DruR Reactions and the Liver (H Davis, JM Treger and Gilliams, eds) pp.95-104, Pitman Medical, London (1981). Waring RH, Mitchell SC, Idle JR, Smith RL. Geneticai:•: determined impaired drug sulphoxidation. Lancet 1981;i:778. 1982 Hetzel MR, Law M, Keal EE, Sloan TP, Idle JR, Smith RL. inbor-: susceptibility/resistance _to lung cancer. In: Cellular BioloQV of the Lunq pp.448-457, Plenum Publishir:: Corporation, Ne:: York (1982). Islam SI, Idle JR. Drug metabolism in arabs - triennial repor: of the joint Jeddah-London Pharmacogenetics Programme. 7th Saudi Medical Meetine, 1982. Kong I, Devonshire H'~:, Cooper `:, Sloan TP, Idle JP., Smith R:,. The infuence of oxidation phenotype on phenacetin metaboiisr and haemotoxicity. Br J Clir. Pharmacol 1982;13:275-276P. lo CTR _ •N 01.M 0*73'

Kupfer A, Al-Dabbagh SC, Ritchie JC, Idle JR, Smith RL. Spectra'_ binding studies of the polymorphically. metabolised dru2s debrisoquine, sparteine and phenformin by cytochrome ?-45C by normal and hydroxylation deficient rat strains. Biochem Pharmacol 1982;31:3193-3199. Mitchell SC, Idle . JR,Smith RL. The metabolism o: 14 ( C)cimetidine in man Xenobiotica 1982;12:283-292. Mitchell SC, Idle JR, Smith RL. Reductive metabolism of cimetidine sulfoxide in man. Drug Metab Dispos 1982;10:2"0z- 290. Mitchell SC, Ritchie JC, Idle JR, Smith RL. Nature of the polar metabolites of inetiamide and cimetidine in man. Biochem Soc Trans 1982;10:123-124. _ Nadir HH, Al-Dabbagh SC, Idle JR. Elevated serum cholesterol i^ drug-oxidation-deficient rats. Biochem Pharmaco: 1982;31:1665-1668. - Oates NS, Shah P.R, Id:e JR, Smith RL. Genetic polyznorphism c: phenformin 4-hydroxvlation. Clin Pharmacol Ther 1982;32:81- 89. Oram M, Wilson K, Burnett D, Al-Dabbagh SC, Idle JR, Smith R:.. Metabolic oxidation of methaqualone in extensive and poor metabolisers of debrisoquine. Eur J Clin Pharmacol 1982;23:147-150. 17 CTR HN 011074,

Osikowska BA, Idle JR, Swinbourne FJ, Sever PS. Uneouivoca: synthesis and characterisation of dopamine 3- and ~ sulphates. Biochem Pharmacol 1982;31:2279-2284. Ritchie JC, Idle JR. Population studies of polymorphism in dr__ oxidation and its relevance to carcinogenesis. In: 'r.es; factors in human carcinogenesis B Armstrong 6'B Bartsch eds. IARC Scientific Publications_,:No.39, Lyon (1982). Shah RR, Oates NS, Idle JR, Smith RL. Beta-Blockers and dr.:: oxidation status Lancet 1982;i:508-509. Shah RR, Oates NS, Idle JR, Smith RL. Impaired oxidation cf debrisoquine in patients with perhexiline neuropathy. B- Med J 1982;284:295-299. Waring RH, Mitchell SC, Shah RR, Idle JR, Smith RL. Polymorp:^.i: sulphoxidation of S-carboxymethyl-L-cysteine in man.Bioche^ Pharmacol 1982; 31: 3151-3154 1983 Devonshire HW, Kong I, Cooper M, Sloan TP, Idle JR, Smith .... The contribution of genetically determined oxidaion status to inter-individual variation in phenacetin dispos•:tion.?= _ Clin Pharmacol 1983; 16: 157-166 Evans DAP, Harmer D, Downham DY, Whiblev EJ, idle JR, Ritc'.^.ie .' , Smith RL. The genetic control of sparteine and debrisoquine in man with new methods of anaivsinQz bimodal distributicns J Med Genet 1983: 20: 321-329. 18 C T R H N 0 110 'r''Es'

Idle JR, Hirom PC, Kirkby CA. Effect of the MO:D locus on the biliary metabolites of benzo(a)pyrene in the rat. In: International Gstaad Symposium, September 1983, 37. Idle JR, Oates NS, Shah RR, Smith RL.• Protecting poor metabolisers, a group at high risk of adverse drug reactions. Lancet 1983; 1: 1388. Idle JR, Ritchie JC. Probing genetically variable carcinogen metabolism using drugs. In: Human Carcinogenesis (C Harris and H Autrup, eds) Academic Press, 1983: 857-881. Idle JR, Sever PS. Treatment of angina pectoris with nifedipine. Br Med J 1983; 286: 1978-1979. Oates NS, Shah RR, Idle JR, Smith RL. Influence of oxidation polymorphism on phenformin kinetics and dynamics. Clin Pharmacol Ther 1983; 34: 827-834. Panayi GS, Hutson G, Shah RR, Mitchell SC, Idle JR, Smith Varing RH. Deficient sulphox.idation status and penicillamine toxicity. Lancet 1983; 1: 414. Ritchie JC, Crothers MJ, Idle JR, Grieg JB, Connors TA, Nikolov IC, Chernozemsky I::. Evidence for an inherited metabo'_ic susceptibility to endemic (Balkan) nephropathy. In: Current research in endemic (Balkan) nenhronathy (S Strahinjic 6V Steefanovic, eds). University Press Nis, 1983: 23-27. 19 CTR HN 011076

Ritchie JC, Mitchell SC, Idle JR, Smith RL. Sex diamorph'_s:^ of metiamide sulphoxidation and glucuronidation in rodent species. Biochem Soc Trans 1983; 11:183-184. Shah RR, Oates NS, Idle JR, Smith RL,.Lockhart JDF. Prediction o: subclinical perhexiline neuropathy in a patient with an inborn error of debrisoquine hydroxylation. Am Heart 1983; 105: 159-161. J Sloan TP, Lancaster R, Shah RR, Idle JR,.Smith RL. Genetically determined oxidation capacity and the disposition o: debrisoquine. Br J C1in Pharmacol 1983; 15: 443-450. 1984 Ayesh R, Idle JR, Ritchie JC, Crothers MJ, Hetzel MR. Metabolic oxidation phenotypes as markers for susceptibility to lung cancer. Nature 1984; 311: 169-170. Emery P, Hutson G, Idle JR, Mitchell SC, Panavi GS, Smith F.-. :.'aring RH. Sulpoxidation status of rheumatoid patients manifesting untoward reactions to chronic therapy. Br J Clin Pharmacol 1984; 18: 286p. D-penicillamine Emery P, Panayi CS, Hutson C, Weish KI, Mitchell SC, Shah RR, Idle JR, Smith RL, Waring RH. D-penicillamine induced toxicity in rheumatoid arthritis: the role of sulphoxidation status and HLA-DR3. J Rheumatol 1984; 11:626-632. Haley CS, Idle JR, Mitchell SC, Smith RL, Waring Pr-i. Heteroatc- 20 ' C~'R ~"g~`~ 01107r

polymorphic drug oxidation - sulphoxidation. Br J C:'_n Pharmacol 1984; 18: 285p-286p. Hietanen E, Malaveille C, Camus A-M, Bereziat JC, Brun C, :d:e JR, Ritchie JC, Bartsch H. Hepatic drug metabolism and S-9 mediated mutagenicity of carcinogens in rat strains characterised as slow.and fast metabolisers of debrisoquine. Hereditas 1984; 100: 177. Idle JR, Smith RL. Protecting the poor metaboliser - from Jack & Wilkins. Br J Clin Pharmacol 1984;.17: 492-495. Mitchell SC, Waring RH, Haley CS, Idle JR, Smith RL. Genetic aspects of the polymodally distributed sulphoxidation of S- carboxymethyl-L-cysteine in man. Br J Clin Pharmacol 198~-: 18: 507-521. Smith RL, Idle JR. The debrisoquine hydroxylation gene : a gene of multiple consequence. Proc Second World Conference o-. Clinical Pharmacology and Therapeutics 1984; 148-164. 1985 Ayesh R, Idle JR. Evaluation of drug oxidation phenotypes in t`:e biochemical epidemiologv of lung cancer risk. In: M.icrosoMes and drug oxidations. ( Boobis A, Caldwell J. De Matteis Elcombe C, eds.) Taylor & Francis, London, 1985: 340-346. Haley CS, Waring RH, Mitchell SC, Shah RR, Idle JR, Smith R:,. Lack of congruence of S-carboxymethYl-L-cysteine sulphoxidation and debrisoquine 4-hydroxyiation in n caucasian population. Xenobiotica 1985; 15: 445-450. 21 CTR l:N 011078

Shah RR, Evans DAP, Oates NS, Idle JR, Smith RL. The gene:'_-- control of phenformin 4-hvdroxylation. J Med Genet 22:361-366. 1986 Hayes RJ, Idle JR. The isolated vas deferens of the whale: responses to electrical stimulation and drugs. J Phvsi--_ 1986; 374: 44P. Ritchie JC, Crothers MJ, Shah RR, Idle JR, Smith RL. ':::e metabolism of debrisoquine in man: (1) regioselectivit:; ..: hydroxylation and (2) aberrant oxidative metabolism in ..c sibling patients with carbimazole-induced agranulocytos'_s. Xenobiotica 1986; 16: 503-509. Mitchell SC, Waring RH, Wilson VL, Idle JR, Autrup H, Harris CC, Ritchie JC, Crothers MJ, Sieber SM. Sulphoxidation of S• carboxymethyl-L-cysteine in the rhesus monkey (Macaca mulatta), cynomologus monkey (Macaca fascicularis), African green monkey (Cerco~ithecus aethioDs) and the mar:rese_ (Callithrix jacchus). ComD Biochem Phvsiol 1986; Hietanen E, Malaveille C, Camus A-M, Bereziat J-C, Brur. C. Castegnaro M, Michelor, J, Idle JP., Bartsch H. Interstra'_-. comparison of hepatic and renal microsomal carcinoge:-n metabolism and liver S-9 mediated mutagenicitv in DA ar.~ Lewis rats phenotyped as poor and extensive metabolizers o= debrisoquine. Druc Metab Dispos 1986; 14: 118-126. Hadidi N, Coulter C, :d:e .,. C.:clophosphamide "metabolic a means of estimating metabolic activation o_ 22 _?e C TR H N 0 110 '~ 9

cyclophosphamide from urine. Abstracts 3rd World Conference of Clinical Pharmacoioev and Therapeutics (Stockholn) '_9"06 Idle J, Hadidi H. Drug interactions with cyclophosphamide metabolism and disposition in mice. Abstracts 3rd wor:d Conference of Clinical PharmacoloQV and Therapeutics (Stockholm) 1986 Perry H, Schmid B, Idle J. Dehydrogenation of nifedipine - fact and artefact. Abstracts 3rd World Conference of Clinical Pharmacology and Therapeutics (Stockholm) 1986 Schmid B, Perry H, Feher M, Sever P, Idle J. Impaired metabo::c dehydrogenation of nifedipine. Abstracts 3rd Wor:d Conference of Clinical Pharmacology and TheraDeutics (Stockholm) 1986 Feher M, Schmid B, Idle J, Sever P. Platelet aggregation and nifedipine plasma concentrations. Abstracts 3rd World Conference of Clinical Pharmacology and Theraoeutics (Stockholm) 1986 Cartmel B, Stockton M, Crothers M, Hadidi H, Idle J, Riordan McNicol M. Distr'_bution of oxidation phenotypes in :Ln_ cancer families. Abstracts 3rd World Conference of Clinica_ PharmacoloQy and Therapeutics (Stockholm) 1986 Crothers H, Cartmel B, Idle J. Chemical and biological stability of the debrisoquine metabolic ratio. Abstracts 3rd World Conference of Clinical Pharmacology and Therapeutics (Stockholm) 1986 Oates N, Crothers M, Shah R, Idle J, Smith R. Influence of dextropropoxyphene on oxidation phenotyping using debrisoquine and phenformin. Abstracts 3rd World Conference 23 CTR HN 011080

of Clinical Pharmacology and Therapeutics (Stockholm) 1986 A1-Waiz M, Mitchell S, Idle J, Smith R. Variation of trimethylamine N-oxidation in man. Abstracts 3rd ;.;o::t Conference of Clinical Pharmacology and TheraDeut'_cs (Stockholm) 1986 Idle J, Nadir H. Oxidation phenotype and urinary 20-hvdroxv- and 17-oxo-steroid profiles,. Abstracts 3rd World Conference of Clinical PharmacoloQy and Therapeutics (Stockholm) 1986 24 CTR HN 011061

PERSONAL REFEREES Professor R.L. Smith Department of Pharmacology St "Sary's Hospital Medical School London W2 1PG Dr.T.A. Connors Director M.R.C. Toxicology Unit Woodmansterne Road Carshalton Surrey Professor M.D. Rawlins _ _ Professor of Clinical Pharmacology Wolfson Unit of Clinical Pharmacology Claremont Place The University Newcastle-upon-Tyne NE1 7RU Dr.C.C. Harris Chief Laboratory of Human Carcinogenesis National Cancer Institute Building 37 Room 2C09 National Institutes of Health Bethesda MA 20205 U.S.A. 25 l.r TR t! 1''4 01106G}