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Environmental and Genetic

Factars in Drug Metabolism

Chairmen:

A. H. CONNEY, USA

R. KATO, Japan

Dedication of the Symposium to

Dr Bernard B. Brodie

All speakers in th is symposium had the privilege of working

with Dr Bernard B. Brodie in his Laboratory of Chemical

Pharmacologyat the National Institutes of Health. We are

grateful to Dr Brodie for that memorable experience which

stimulated our interest in drug metabolism and the factors

that regulate it. Because of the many fundamental

contributions made by Dr Brodie to th is field, and because

of the impact Dr Brodie had on our own research, we

dedicate th is symposium to him. Th is dedication is

particularly appropriate because the symposium was held

on August 7, Dr Brodie's birthday.

A. H. Conney

R. Kato

J. R. Mitchell

R. L. Smith

E. S. Vesell

August, 1980

London

VARIABILITY IN

HUMAN DRUG METABOLISM

A.H.CONNEY

Departm ent 0/Biochemistry and Drug Metabolism ,

Hoffmann-La Roche ln c.,

N utley, New Jersey 07110. USA

E.J. PANTUCK&C. B. PANTUCK

Department 0/ Anesthesiology,

College 0/Physician s and Surgeons,

Columbia University,

Ne w York, New York 10032. USA

J. G. FORTNER

M em orial Sloan-Kettering Can cer Center,

New York, Ne w York 10021. USA

A. P. ALVARES

Department 0/Pha rmacology,

Uniform ed Services University ofthe Health Sciences,

Bethesda, Ma ryland 20014. USA

K. E. ANDERSON & A. KAPPAS

The Rockefeller University,

Ne w York, Ne w York 10021. USA

Individual differenees in the response of peop le to a drug and variability in the

response that oeeurs when patients are given a drug on several oeeasions are

important problems in c1 inieal pharmaeology. Indeed , variability in the responsiv eness of all living organisms to toxie ehemieals has general importanee in biology.

Individuality in the responsiveness ofhumans to drugs and environmental ehemieaI s

is eaused , in part, by differenees in rates of ehemical biotransformations in different

indiv iduals . In the present report, some studies on interindividual and intraindividual differenees in the metabolism of foreign ehemieals in humans and the

effeets ofdietary faetors on the metabolism ofthese substanees in man are deseribed.

52 A. H. CONNEY et al.

Interindividual differences in the metabolism offoreign chemieals

A number of years ago, the metabolism ofsome drugs and carcinogens by sampies of

human liver obtained during abdominal surgery was investigated. Variability in the

catalytic activity ofsampies from different individuals was found (Kuntzman, Mark,

Brand, Jacobson, Levin & Conney, 1966). More recent studies indicated marked

differences in the ability of liver sampies from different individuals to metabolize

benzo[a]pyrene, antipyrine, hexobarbitone, coumarin, aflatoxin BI, and

benzo[a]pyrene 7,8-dihydrodiol (Conney, Pantuck, Pantuck, Buening, Jerina,

Fortner, Alvares, Anderson & Kappas, 1979). Aflatoxin BI (a potent liver carcinogen)

and benzo[a]pyrene 7,8-dihydrodiol (a proximate carcinogenic metabolite of

benzo[a]pyrene) are both metabolized to chemically reactive metabolites by

microsomal enzymes before exerting their mutagenic and carcinogenic effects (Miller

& Miller, 1977a, 1977b; Conney, Levin, Wood, Yagi, Lehr & Jerina, 1978; Jerina,

Yagi , Thakker, Karle, Mah, Boyd, Gadaginamath, Wood, Buening, Chang, Levin &

Conney, 1978). A nine-fold difference in the metabolism of aflatoxin BI to mutagens

and a seven-fold difference in the metabolism of benzo[a]pyrene 7,8-dihydrodiol to

mutagens were observed among the ten liver sampies studied (Figure I). Similar

differences were observed in the metabolism of benzo[a]pyrene to phenolic

metabolites by the different liver sampies (Figure I). Individuality in the metabolism

ofbenzo[a]pyrene, benzo[a]pyrene 7,8-dihydrodiol, and aflatoxin BI to their reactive

metabolites may help explain individual differences in the sensitivity ofpeople to the

carcinogenic action ofthese chemicals.

Large interindividual differences occur for the metabolism of benzo[a]pyrene by

human placenta (Welch, Harrison, Conney, Poppers & Finster, 1968; Welch,

Harrison, Gommi, Poppers, Finster & Conney, 1969), cultured human skin (Levin,

Conney, Alvares, Merkatz & Kappas, 1972; Alvares, Kappas, Levin & Conney,

1973), human macrophages (Cantrell, Warr, Busbee & Martin, 1973), cultured

human lyrnphocytes (Busbee, Shaw & Cantrell, 1972; Kellermann, LuytenKellerman & Shaw, 1973), monocytes (Bast , Whitlock, Miller, Rapp & Gelboin,

1974), bronchial cells (Harris, Autrup, Connor, Barrett, Mcfrowell & Trump, 1976;

Harris, Autrup, Stoner, Yang, Leutz, Gelboin, Selkirk, Connor, Barrett, Jones,

McDowell & Trump, 1977), and pancreatic duct cells (Harris et al., 1977). Large

interindividual differences also occur in the metabolism of dimethylhydrazine by

human colon explants (Autrup, Trump, Smith & Harris, 1980), and in the

metabolism of dimethylnitrosamine by human liver (Czygan, Greim, Garro,

Hutterer, Rudick, Schaffner & Popper, 1973). Although cigarette smoking markedly

stimulated benzo[a]pyrene hydroxylase activity in human placenta, there was a

70-fold difference in the enzyme activities ofplacentas from women who smoked the

same number ofcigarettes (Welch et a/., 1969). A 150-fold difference was observed for

the metabolism of benzo[a]pyrene to DNA-bound adducts by cultured bronchial

explants from different individuals (Harris, Autrup, Trump, McDowell, Apostolides

& Schafer , 1980), and a 100-fold difference was observed for the metabolism of

1,2-dimethylhydrazine to DNA-bound adducts by cultured colon explants from

different individuals (Autrup et al., 1980).

Studying the comparative metabolism of drugs and environmental carcinogens by

human liver in vitro is an approach for identifying drugs that are metabolized by the

same enzyme system(s) that metabolize(s) the carcinogen. The extent of first pass

metabolism or the half-life of a nontoxic drug that is metabolized by the same

enzyme system(s) that metabolize(s) an environmental carcinogen may serve as an

indirect index of an individual's ability to metabolize the carcinogen, and metabolic

studies with appropriate drugs may help to determine the potential hazard in

different individuals of exposure to the carcinogen. This approach for identifying

VARIABILITY IN HUMAN DR UG MET ABOLISM 53

His+ revertants mg-I

o

o

o

N

o

o

o

'"o

o

o

l>

o

o

o

I I

CD....

o

Cl ,,=",__

n=

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His+ revertants mg- I

o

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o

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o

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CD

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0 0

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-e

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CD

n

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Figure 1 Interindivid ual difTerenees in the metabolism of allatoxin B. benzo(a]pyrene

7,8-dihydrodiol and benzo(a]pyrene by mierosomes from sampies of human liver obtained

during abdominal surgery. All the liver sampies studied had normal histology. Metabolism of

benzo(a]pyrene to fluoreseent phenols and the metabolie aetivation of aflatoxin B, and

benzo[a)pyrene 7,8-dihydrodiol to rnutagens were measured. Taken from data by Conney eral.

(1979)and Conney (1980).

54 A. H. CONNEY et al.

individuals with an unusually high risk towards environmental carcinogens has been

summarized elsewhere (Conney, 1980).

Many exogenous chemieals such as drugs (Conney, 1967), alcohol (Misra, Lefevre,

Ishii, Rubin & Lieber, 1971; Iber, 1977), cigarette smoke (Pantuck, Kuntzman &

Conney, 1972; Pantuck, Hsiao, Maggio, Nakamura, Kuntzman & Conney, 1974;

Conney et al.. 1977), insecticides (Kolmodin, Azarnoff & Sjöqvist, 1969; Poland,

Smith, Kuntzman, Jacobson & Conney, 1970), polychlorinated biphenols (Alvares,

Fischbein, Anderson & Kappas, 1977), lead (Alvares, Kapelner, Sassa & Kappas,

1975; Alvares, Fischbein, Sassa , Anderson & Kappas, 1976b; Meredith, Campbell,

Moore & Goldberg, 1976) and certain dietary constituents (Alvares, Anderson,

Conney & Kappas, 1976a; Conney, Pantuck, Hsiao, Garland, Anderson, Alvares &

Kappas, 1976; Kappas, Anderson, Conney & Alvares, 1976; Kappas, Alvares,

Anderson, Pantuck, Pantuck, Chang & Conney, 1978; Pantuck, Hsiao, Conney,

Gariand, Kappas, Anderson & Alvares, 1976; Pantuck, Pantuck, Gariand, Min ,