Tobacco Documents Online

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