Title Page Cigarette Smoking, Coffee Drinking, and Ingestion of ...

JPET Fast Forward. Published on April 18, 2012 as DOI:10.1124/jpet.112.193193 

Title Page 

1 

JPET #193193 PiP 

Cigarette Smoking, Coffee Drinking, and Ingestion of Charcoal-broiled Beef as 

Potential Modifiers of Drug Therapy and Confounders of Clinical Trials 

A. H. Conney, Ph.D. and M. M. Reidenberg, MD 

Affiliations: 

Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical 

Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New 

Jersey; Laboratory of Natural Medicinal Chemistry & Green Chemistry, Guangdong 

University of Technology, Guangzhou, China. (AHC) 

Weill Cornell Medical College, 1300 York Ave., New York, NY 10065 (MMR) 

Copyright 2012 by the American Society for Pharmacology and Experimental Therapeutics.

Running Title Page 

Running title: Polycyclic hydrocarbons and drug metabolism 

Corresponding author: 

Allan H. Conney, Susan Lehman Cullman Laboratory for Cancer Research, 

2 


Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The 

State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854 

Phone: 732-445-4940, Fax: 732-445-0687, Email: aconney@pharmacy.rutgers.edu 

The number of text pages: 11 

The number of tables: 3 

The number of figures: 4 

The number of references: 43 

The number of words in the Abstract: 105 

Number of words in the text: 3,009

Abstract 

3 


A pathway of research is described leading from the finding of an inhibitory effect of 

3-methylcholanthrene on the carcinogenicity of an aminoazo dye, to the induction of 

drug-metabolizing enzymes by 3-methylcholanthrene, benzo[a]pyrene and other 

polycyclic aromatic hydrocarbons, to the demonstration of enhanced drug 

metabolism in cigarette smokers, coffee drinkers and in people eating charcoal- 

broiled beef. The results of these studies indicate that cigarette smoking, coffee 

drinking and the ingestion of charcoal-broiled beef (all result in exposure to 

polycyclic aromatic hydrocarbons) can influence the dosing regimen needed for 

proper drug therapy and are potential confounders of clinical trials with drugs 

metabolized by polycyclic aromatic hydrocarbon-inducible enzymes.

It is well known that there are large differences in the dose-response 

4 


relationship of drugs from one person to another that are dependent on both 

genetic and environmental factors that influence drug metabolism. Although 

genotyping patients for drug-metabolizing enzymes prior to drug therapy can help 

establish a proper initial dosing regimen for individual patients, environmental 

modulation of drug metabolism is also important and requires a different approach 

for establishing a proper dosing regimen. 

Early research by H.L. Richardson demonstrated that administration of the 

carcinogen 3-methylcholanthrene to rats unexpectedly inhibited the 

hepatocarcinogenicity of an aminoazo dye (Richardson et al, 1952). This report was 

followed by a research program that showed why a carcinogenic polycyclic aromatic 

hydrocarbon (PAH) inhibited the tumorigenicity of a carcinogenic aminoazo dye and 

provided a springboard that led to research showing stimulatory effects of cigarette 

smoking, the eating of charcoal-broiled beef, and coffee drinking on the metabolism 

of certain drugs. In these early studies, it was demonstrated that administration of 

3-methylcholanthrene, benzo[a]pyrene or several other PAHs induced the synthesis 

of hepatic enzymes that metabolized aminoazo dyes to noncarcinogenic products 

(Brown et al, 1954; Conney, 1954; Conney et al, 1956). This work, which was done 

more than 50 years ago, was the first demonstration of the induction of xenobiotic- 

metabolizing enzymes and led to further research demonstrating a stimulatory 

effect of administration of benzo[a]pyrene and other PAHs on the metabolism of 

several drugs and to the finding of stimulatory effects of cigarette smoking,

5 


ingestion of charcoal-broiled beef and coffee drinking on drug metabolism in 

animals and humans. 

The stimulatory effect of i.p. injections of 3-methylcholanthrene on the oxidative 

N-demethylation and the reductive cleavage of aminoazo dyes to noncarcinogenic 

metabolites by the liver is shown in Fig 1 (Brown et al, 1954; Conney, 1954; Conney 

et al, 1956), and the stimulatory effect of benzo[a]pyrene on its own metabolism 

and on the hepatic metabolism of the muscle relaxant drug zoxazolamine is shown 

in Fig. 2 (Conney et al, 1960; Conney et al, 1959; Conney et al, 1957). A single i.p. 

injection of benzo[a]pyrene 24 hr prior to administration of zoxazolamine had a 

dramatic stimulatory effect on the in vivo metabolism of this drug (Fig 2), and the 

duration of action of zoxazolamine was decreased from 730 min to only 17 min 

(Conney et al, 1960). Studies on the enzyme-inducing activity of a large number of 

PAHs indicated that many environmental PAHs with 4 or more rings when 

administered by i.p. injection to rats are potent inducers of hepatic aminoazo dye N- 

demethylase (Arcos et al, 1961). Modest inducing activity was also observed in mice 

fed 3-methylcholanthrene, benz[a]anthracene, pyrene or phenanthrene for one 

week (Brown et al, 1954; Conney, 1954). Later studies indicated that PAHs were 

potent inducers of cytochromes P450 1A1 and 1A2. Since PAHs that induce certain 

drug-metabolizing enzymes are present in tobacco smoke and in charcoal-broiled 

beef (Table 1) (Hoffmann et al, 1978; Lijinsky et al, 1964), the effects of cigarette 

smoking and eating charcoal-broiled beef on the metabolism of substances that are 

metabolized by PAH-inducible enzymes were evaluated in humans.

6 


Cigarette smokers had greatly elevated levels of placental benzo[a]pyrene 

hydroxylase, aminoazo dye N-demethylase and zoxazolamine hydroxylase activities 

(Table 2) (Kapitulnik et al, 1976; Welch et al, 1968; Welch et al, 1969), which are 

PAH-inducible enzymes in rodents. In additional studies, cigarette smoking or eating 

charcoal-broiled beef lowered the plasma levels of phenacetin (a CYP1A1/2 

substrate) without altering its half-life (Fig 3) (Conney et al, 1976; Pantuck et al, 

1976; Pantuck et al, 1974a; Pantuck et al, 1972). In these studies, the ratio of N- 

acetyl-p-aminophenol (phenacetin’s major metabolite) to phenacetin was increased 

by 2- to 5-fold at the different time intervals after administration of phenacetin, and 

it was suggested that cigarette smoking or eating charcoal-broiled beef enhanced 

the intestinal metabolism of phenacetin. In accord with this concept, administration 

of benzo[a]pyrene, exposure to cigarette smoke, or the feeding of charcoal-broiled 

beef stimulated the metabolism of phenacetin by rat intestine (Pantuck et al, 1975; 

Pantuck et al, 1974a; Pantuck et al, 1974b). It is likely that eating other charcoal- 

broiled foods such as charcoal-broiled chicken or fish will also stimulate the 

metabolism of drugs that are metabolized by PAH-inducible enzymes. 

PAHs are formed during the roasting of coffee beans (Houessou et al, 2007), and 

the concentrations of various PAHs in several coffee brews are shown in Table 3 

(Orecchioa et al, 2009). Administration of coffee to rats increased the level of 

hepatic CYP1A2, and this effect of coffee was partially lost in decaffeinated coffee 

suggesting that both caffeine and non-caffeine components (probably PAHs) play a 

role for the effect of coffee administration to increase the level of hepatic CYP1A2 in 

rats (Turesky et al, 2003). A recent study indicates that coffee drinkers have

7 


enhanced 3-demethylation of caffeine, which occurs predominately by CYP1A2 

(Djordjevic et al, 2008). About 5-10% of commonly prescribed drugs undergo 

metabolism by CYP1A2. Examples of drugs that are metabolized to a significant 

extent by CYP1A2 include caffeine, theophylline, phenacetin (no longer marketed), 

tizanidine, clozapine, fluvoxamine, olanzapine, zoxazolamine (no longer marketed), 

and tacrine. In summary, cigarette smoking, coffee drinking, and the ingestion of 

charcoal-broiled beef can stimulate drug metabolism, alter the dosing regimen 

needed for proper drug therapy, and these modifiers of drug metabolism are 

potential confounders during clinical trials with drugs that are metabolized by PAH- 

inducible enzymes. 

Other sources of environmental exposure to PAHs are from the burning of coal, 

wood and gasoline as well as from petroleum refining so that people heavily 

exposed to these sources of PAHs would be expected to have enhanced metabolism 

of drugs that are metabolized by cytochromes P450 1A1 and 1A2. 

These data on common environmental factors which increase the rate of drug 

metabolism raise three important clinical concerns: 

The first concern is related to the variability of dose-response among different 

individuals in a population. This is especially relevant in a clinical trial. Fig. 4 

(Asberg, 1974) shows the range of concentrations of nortriptyline in the plasma of 

248 people taking 150 mg/d of the drug. This greater than 6 fold range from the 

lowest to the highest concentration is representative of what occurs with many 

drugs eliminated by metabolism. In an additional study, the plasma level of 

desmethylimipramine varied by 36-fold in eleven different individuals receiving the

8 


same 75mg daily dose of the drug (Hammer et al, 1967). Although variability in the 

metabolism of nortriptyline and desmethylimipramine that occurs in different 

individuals is related primarily to genetic polymorphisms in CYP2D6, the 

metabolism of these compounds can also be regulated by environmental factors, 

and person-to-person differences in plasma levels described in Fig. 4 illustrate 

variability in metabolism that can occur from both genetic and environmental 

factors that regulate drug metabolism. For nortriptyline, the best efficacy is when 

the concentration is 50-140 ng/ml (Asberg et al, 1971) or about a 3 fold range. 

While the dose of 150 mg/d had most patients in this range, many patients had 

lower or higher levels causing less efficacy or increased risk of an adverse effect, 

respectively. Adjusting the dose to allow for a person’s rate of metabolism can bring 

the drug level into the therapeutic range with the intended intensity of effect. One 

study of only 10 patients receiving a dose of 8mg tizanidine found a mean peak 

concentration of 25 pg/ml with a range of 15-43 pg/ml, a 3 fold range in only 10 

patients (Mathias et al, 1989). Since induction speeds drug metabolism, an induced 

population of subjects in a trial will lack the very slow metabolizers that occur in the 

general population. The trial will fail to detect subjects who would have had high 

drug levels at the studied dose if they were not induced. The interpretation of the 

trial will be that the observations represent the drug levels and effects of this dose 

for the general population. It will fail to recognize that the fraction of the population 

that are un-induced slow metabolizers will have higher levels than seen in the trial 

and possibly overdose at the studied dose. Thus, unanticipated toxicity may occur 

after marketing.

9 


A second concern relates to the size of the population needed to determine the 

effectiveness of an agent being studied in a clinical trial. The presence of a moderate 

number of individuals with induced drug-metabolizing activity may magnify 

variability of response in the population studied thereby requiring more subjects to 

determine effectiveness of the substance being evaluated. Measurement of blood or 

saliva levels of drug during the course of the trial will help in interpretation of the 

trial. 

A third concern relates to patient care. A person taking a medicine who then 

ingests an inducer may have an increase in the rate of drug metabolism. The extent 

of the increase depends on the dose of inducer and the sensitivity of the person to it 

(Mathias et al, 1989). This induction will increase the rate of metabolism of the drug 

and decrease the drug level and efficacy and benefit from taking the medicine. If the 

dose is then raised to allow for the new rate of metabolism and the inducer is 

subsequently stopped, such as when the patient finally quits smoking or stops 

charcoal-broiling or drinking coffee, the induced state will subside and the drug 

level and intensity of effect will go up. Toxicity may follow if the dose is not reduced. 

This was reported for a patient taking clozapine and another taking olanzapine. 

Each stopped smoking and developed toxicity from their medicine (Breckenridge et 

al, 1973). 

Research in patients has found that smokers have lower concentrations of many 

of the clinically important drugs metabolized by PAH-inducible enzymes than 

nonsmokers when given the same dose. This has been shown for haloperidol (Jann 

et al, 1986) and tacrine (Zevin et al, 1999). Other examples are: fluvoxamine levels

10 


in smokers are 1/3 that of nonsmokers (Spigset et al, 1995), clozapine levels are 1/3 

lower for men, 1/5 for women compared to nonsmokers (Haring et al, 1989), and 

smoker olanzapine levels are 1/5 that of nonsmokers (Carrillo et al, 2003). Clearly 

cessation of smoking can cause “overdose” toxicity for a patient taking any of these 

medications and then stops smoking. 

Thus, the experimental animal studies indicating an inhibitory effect of one 

carcinogen (a polycyclic aromatic hydrocarbon) on the action of another carcinogen 

(an aminoazo dye) led to additional research demonstrating polycyclic aromatic 

hydrocarbon-induced synthesis of drug-metabolizing enzymes that has relevance 

for clinical trials and for the care of sick people. 

Perspectives for the future 

Although we have focused in the present article on early basic research that 

led to the discovery of the effects of cigarette smoking, coffee drinking and charcoal- 

broiled beef ingestion on drug metabolism in humans, there are many factors that 

influence rates of drug metabolism that are important for explaining differences in 

drug response in different individuals receiving the same dose of drug and in the 

same individual on different occasions. In earlier studies, we found substantial 

differences in the metabolism of phenacetin in individuals leading an unrestricted 

life-style when given phenacetin on several occasions over a several month period 

(Conney et al, 1979). Factors affecting drug metabolism in humans include genetic 

factors (polymorphisms such as mutations, insertions, deletions, and gene

11 


duplications), epigenetic factors (gene methylations, histone acetylation), disease 

states (liver disease, kidney disease, and viral infections), and a variety of 

environmental factors (cigarette smoking, coffee drinking, alcohol consumption, 

drug administrations/drug interactions, herbal remedies such as St. Johns wort, 

exposure to DDT or gasoline fumes as observed in gasoline station attendants, and 

dietary factors such as the ratio of protein to carbohydrate, cruciferous vegetables, 

charcoal-broiled beef, and grapefruit juice). Although genotyping individuals for the 

cytochrome P450s or other drug-metabolizing enzymes has been helpful in 

identifying genetically determined poor or rapid metabolizers of many drugs, the 

prevalence of environmental factors that influence drug metabolism suggests the 

importance of drug level monitoring for effective therapy. 

Measurement of drug levels 

Prior to the initiation of an extensive program for drug level monitoring to 

guide the dosing regimen in individual patients, there is a need for further research 

to develop simple, rapid and inexpensive blood or saliva drug level tests that can 

be utilized and evaluated rapidly during each visit to the patient’s physician or 

during the monitoring of clinical trials. These tests could be developed by 

pharmaceutical companies that develop the drugs, and this activity could develop 

into a new business for the pharmaceutical industry that would help achieve more 

effective drug therapy. To achieve rapid information on blood or saliva drug levels 

and an appropriate starting dosing regimen, the analysis of samples by high

12 


sensitivity and specific methodology should be done and interpreted rapidly at the 

point of care. 

Although we are suggesting a greater emphasis on the use of blood or saliva 

drug level monitoring for measuring rates of drug metabolism and effective drug 

use, more attention should also be given to variations in drug transporters and their 

importance for person-to-person differences in drug response. Some drugs interact 

with transporters that modify the drug’s passage into tissues and the drug’s ability 

to reach receptors so that measuring blood levels of these drugs may not be a good 

index for the amount of drug that reaches a receptor. Both genetic and 

environmental factors influence the level or function of transporters (Nakanishi et 

al, 2012; Sissung et al, 2012; Wang et al, 2007; Wesołowska, 2011) so that 

developing methods for evaluating the levels or effects of these transporters by 

suitable methodology in humans will be important. Can we develop imaging 

methods that will allow us to measure drug levels at or near receptors? Finally, it 

would be an important advance to develop pharmacologically active drugs that 

don’t undergo substantial metabolism but are excreted unchanged. It is likely that 

these drugs would be highly water soluble and excreted by the kidney with less 

person-to-person variations in blood levels and action than drugs that undergo 

metabolism. Variation of elimination rates of drugs excreted unchanged by the 

kidney is related to renal function. This is easily estimated by present methods. 

Since highly water-soluble drugs are poorly absorbed, the use of lipophilic prodrugs 

such as esters that would be readily absorbed and rapidly metabolized by tissue 

esterases prior to excretion by the kidney is a possible approach.

Clinical trials 

13 


Clinical trials can be made more efficient by enriching the study population in 

3 ways: selecting subjects (a) that are likely to have the condition or event being 

treated or prevented, (b) that are likely to respond to the intervention, and (c) 

reducing the heterogeneity of the subject population (Temple, 2010). A way to 

decrease heterogeneity caused by enzyme induction and the other causes of 

differences in the rate of elimination of the study drug is by doing a concentration- 

controlled clinical trial rather than the usual dose-controlled trial. In the 

concentration-controlled trial, the investigators determine what concentrations of 

drug in plasma they wish to evaluate, measure drug concentrations in the subjects 

early in the trial and then adjust the dose for each subject to achieve the desired 

concentration (Kraiczi et al, 2003). 

Medical practice 

In medical practice, the use of drug concentration measurements to adjust 

dose for individual patients has been in use for over 40 years since Kutt and 

McDowell showed the value of this in adjusting the dose of phenytoin in patients 

with epilepsy in 1968 (Kutt et al, 1968). Despite this lengthy experience with using 

drug levels to adjust dose to achieve the desired intensity of effect, many areas of 

medical practice remain in which this concept of adjusting the dose to correct for an 

individual’s un-average pharmacokinetics is underutilized. For example, patient-

14 


controlled analgesia (PCA) is now commonly used to treat postoperative pain. The 

patient pushes a button on an electronic device when a supplemental dose of an 

analgesic is desired. The device then administers a prespecified dose of medicine 

usually by injection into an ongoing intravenous infusion. This PCA corrects for both 

pharmacokinetic variability affecting dose to drug level relationships and the 

variation of drug level to intensity of effect relationships. It is a way to individualize 

or personalize drug therapy. It is clear that both types of variability affect the dose- 

response relationships. Yet despite all this knowledge about individualizing dosage, 

at least for the pharmacokinetic variability, it is rarely done in managing chronic or 

cancer pain in ambulatory practice. One reason is lack of readily available 

measurements of opioid analgesics. For example, a research study done with 

hospitalized patients receiving opioids for chronic severe pain found that 60% of 

patients with bone or soft tissue pain had plasma opioid concentrations lower than 

the lowest concentration in patients having pain relief (Reidenberg et al, 1988). 

There are large person-to-person differences in the metabolic inactivation of 5- 

fluorouracil (FU) by dihydropyrimidine dehydrogenese, and a recent study utilizing 

blood level monitoring to adjust dosing regimens throughout drug therapy was 

shown to improve therapy. The investigators indicated that “individual FU dose 

adjustment based on pharmacokinetic monitoring resulted in significantly improved 

objective response rate, a trend to higher survival rate, and fewer grade 3 or 4 

toxicities. These results support the value of pharmacokinetically guided 

management of FU dose in treatment of metastatic colorectal cancer patients” 

(Gamelin et al, 2008).

15 


Many drugs have large inter-individual differences in rates of elimination 

with plasma concentrations ranging from ineffective through therapeutic to toxic at 

standard dose. Individualizing doses to achieve the desired or therapeutic drug 

concentrations will get patients at the extremes of the elimination rate distribution 

into the therapeutic range with better outcomes for these patients. 

To put the knowledge and concepts of pharmacology explaining some 

reasons for individual variability of dose-response into practice, better methods of 

measuring drug concentrations in plasma, especially at the point of care, are needed. 

When these measurements should be made, such as early in therapy or at steady 

state, depends on the specifics of the drug and disease being treated. By applying 

our knowledge to control for the pharmacokinetic variability from patient to 

patient, the response can be made more predictable. And when it is more 

predictable, drug therapy is both safer and more effective. 

Authorship Contributions 

Performed data analysis: Conney and Reidenberg 

Wrote or contributed to the writing of the manuscript: Conney and Reidenberg

References 

16 


JC, Conney AH, Buu-Hoi NP (1961) Induction of microsomal enzyme synthesis 

Arcos 

polycyclic aromatic hydrocarbons of different molecular sizes. J Biol Chem 

by 

236: 1291-1296. 

M (1974) Individualization of treatment with tricyclic compounds, in 

Asberg 

MM, editor. Med Clin North Am 1083-1091. 

Reidenberg 

M, Cronholm B, Sjoqvist F, Tuck D (1971) Relationship between plasma level 

Asberg 

therapeutic effect of nortriptyline. Br Med J 3: 331-334. 

and 

A, Orme LE, Davies L, Thorgeirsson SS, Davies DS (1973) Dose- 

Breckenridge 

enzyme induction. Clin Pharmacol Ther 14: 514-520. 

dependent 

R, Miller JA, Miller EC (1954) The metabolism of methylated aminoazo dyes 

Brown 

Dietary factors enhancing demethylation in vitro. J Biol Chem 209: 211- 

IV. 

222. 

JA, Herráiz AG, Ramos SI, Gervasini G, Vizcaíno S, Benítez J (2003) Role of 

Carrillo 

smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 

the 

steady-state concentration of olanzapine. J Clin Psychopharmacol 23: 119- 

in 

127. 

AH (1954) Studies on the demethylation and reduction of aminoazo dyes. 

Conney 

thesis, Memorial Library, University of Wisconsin, Madison 

Masters 

AH, Davison C, Gastel R, Burns JJ (1960) Adaptive increases in drug- 

Conney 

enzymes induced by phenobarbital and other drugs. J 

metabolizing 

Pharmacol Exp Ther 130: 1-8. 

AH, Gillette JR, Inscoe JK, Trams ER, Posner HS (1959) Induced synthesis of 

Conney 

microsomal enzymes which metabolize foreign compounds. Science 

liver 

130: 1478-1479. 

AH, Miller EC, Miller JA (1956) The metabolism of methylated aminoazo 

Conney 

V. Evidence for induction of enzyme synthesis in the rat by 3- 

dyes. 

methylcholanthrene. Cancer Res 16: 450-459. 

AH, Miller EC, Miller JA (1957) Substrate-induced synthesis and other 

Conney 

of benzpyrene hydroxylase in rat liver. J Biol Chem 228: 753-766. 

properties

17 


AH, Pantuck EJ, Hsiao K-C, Garland WA, Anderson KE, Alvares AP, Kappas A 

Conney 

Enhanced phenacetin metabolism in human subjects fed charcoal- 

(1976) 

broiled beef. Clin Pharmacol Ther 20: 633-642. 

AH, Pantuck EJ, Pantuck CB, Buening MK, Jerina DM, Fortner JG, Alvares AP, 

Conney 

KE, Kappas A (1979) Role of environment and diet in the 

Anderson 

of human drug metabolism in The Induction of Drug Metabolism 

regulation 

R W and Lindenlaub E eds) pp 583-605, F. K. Schattauer Verlag, 

(Estabrook 

New York. 

N, Ghotbi R, Bertilsson L, Jankovic S, Aklillu E (2008) Induction of 

Djordjevic 

by heavy coffee consumption in Serbs and Swedes. Eur J Clin 

CYP1A2 

Pharmacol 64: 381-385. 

E, Delva R, Jacob J, Merrouche Y, Raoul JL, Pezet D, Dorval E, Piot G, Morel A, 

Gamelin 

M (2008) Individual fluorouracil dose adjustment based on 

Boisdron-Celle 

follow-up compared with conventional dosage: Results of a 

pharmacokinetic 

randomized trial of patients with metastatic colorectal cancer. J 

multicenter 

Clin Oncol 26: 2099-2105. 

W, Idestrom CM, Sjöqvist F (1967) Chemical control of antidepressant drug 

Hammer 

International Congress Series No 122, Proceedings of the First 

therapy. 

Symposium on Antidepressant Drugs, Milan, 25-26 April, 1966 

International 

by S. Garattini and M.N.G. Dukes. Amsterdam C, Netherlands: Excerpta 

Edited 

Medica. 301-310. 

C, Meise U, Humpel C, Saria A, Fleischhacker WW, Hinterhuber H (1989) 

Haring 

plasma levels of clozapine: influence of smoking behaviour, sex 

Dose-related 

and age. Psychopharmacology (Berl) 99: S38-S40. 

D, Schmeltz I, Hecht SS, Wynder EL (1978) Tobacco Carcinogenesis. In: 

Hoffmann 

Hydrocarbons and Cancer, Vol 1, (eds HV Gelboin and POP Ts'o), 

Polycyclic 

Academic Press pp85-117. 

JK, Maloug S, Leveque A-S, Delteil C, Heyd B, Camel V (2007) Effect of 

Houessou 

conditions on the polycyclic aromatic hydrocarbon content in 

roasting 

ground arabica coffee and coffee brew. J Agric Food Chem 55: 9719-9726. 

MW, Saklad SR, Ereshefsky L, Richards AL, Harrington CA, Davis CM (1986) 

Jann 

of smoking on haloperidol and reduced haloperidol plasma 

Effects 

and haloperidol clearance. Psychopharmacology (Berl) 90: 

concentrations 

468-470.

18 


J, Levin W, Poppers PJ, Tomaszewski JE, Jerina DM, Conney AH (1976) 

Kapitulnik 

of the hydroxylation of zoxazolamine and benzo[a]pyrene in 

Comparison 

placenta: Effect of cigarette smoking. Clin Pharmacol Ther 20: 557- 

human 

564. 

H, Jang T, Ludden T, Peck CC (2003) Randomized concentration-controlled 

Kraiczi 

motivations, use, and limitations. Clin Pharmacol Ther 74: 203-214. 

trials: 

H McDowell F (1968) Management of epilepsy with diphenylhydantoin sodium: 

Kutt 

regulation for problem patients. JAMA 203: 969-972. 

Dosage 

W Shubik P (1964) Benzo[a]pyrene and other polynuclear hydrocarbons in 

Lijinsky 

broiled steaks. Science 145: 53-55. 

charcoal 

CJ, Luckitt J, Desai P, Baker H, el Masri W, Frankel HL (1989) 

Mathias 

and pharmacokinetics of the oral antispastic agent 

Pharmacodynamics 

tizanidine in patients with spinal cord injury. J Rehabil Res Dev 26: 9-16. 

T Tamai I (2012) Genetic polymorphisms of OATP transporters and their 

Nakanishi 

on intestinal absorption and hepatic disposition of drugs. Drug Metab 

impact 

Pharmacokinet 27: 106-121. 

S, Ciottib VP, Culottac L (2009) Polycyclic aromatic hydrocarbons (PAHs) 

Orecchioa 

coffee brew samples: Analytical method by GC–MS, profile, levels and 

in 

sources. Food & Chemical Toxicology 47: 819-826. 

EJ, Hsiao K-C, Conney AH, Garland WA, Kappas A, Anderson KE (1976) 

Pantuck 

of charcoal-broiled beef on phenacetin metabolism in man. Science 

Effect 

194: 1055-1057. 

EJ, Hsiao K-C, Kuntzman R, Conney AH (1975) Intestinal metabolism of 

Pantuck 

in the rat: Effect of charcoal-broiled beef and rat chow. Science 

phenacetin 

187: 744-746. 

EJ, Hsiao K-C, Maggio A, Nakamura K, Kuntzman R, Conney AH (1974a) 

Pantuck 

of cigarette smoking on phenacetin metabolism. Clin Pharmacol Ther 

Effect 

15: 9-17. 

EJ, Hsiao KC, Kaplan SA, Kuntzman R, Conney AH (1974b) Effects of enzyme 

Pantuck 

on intestinal phenacetin metabolism in the rat. J Pharmacol Exp 

induction 

Ther 191: 45-52. 

EJ, Kuntzman R, Conney AH (1972) Decreased concentration of phenacetin 

Pantuck 

plasma of cigarette smokers. Science 175: 1248-1250. 

in

19 


MM, Goodman H, Erle H, Gray G, Lorenzo B, Leipzig RM, Meyer BR, 

Reidenberg 

DE (1988) Hydromorphone levels and pain control in patients with 

Drayer 

severe chronic pain. Clin Pharmacol Ther 44: 376-382. 

HL, Stier AR, Borsos-Nacht-Nebel E (1952) Liver tumor inhibition and 

Richardson 

histologic responses in rats to which 3'-methyl-4- 

adrenal 

and 20-methylcholanthrene were simultaneously 

dimethylaminoazobenzene 

Cancer Res 12: 356-361. 

administered. 

TM, Troutman SM, Campbell TJ, Pressler HM, Sung H, Bates SE, Figg WD 

Sissung 

Transporter pharmacogenetics: transporter polymorphisms affect 

(2012) 

physiology, diseases, and pharmacotherapy. Discover Medicine 13: 

normal 

19-34. 

O, Carleborg L, Hedenmalm K, Dahlqvist R (1995) Effect of cigarette smoking 

Spigset 

fluvoxamine pharmacokinetics in humans. Clin Pharmacol Ther 58: 399- 

on 

403. 

R (2010) Enrichment of clinical study populations. Clin Pharmacol Ther 88: 

Temple 

774-778. 

RJ, Richoz J, Constable A, Curtis KD, Dingley KH, Turteltaub KW (2003) The 

Turesky 

of coffee on enzymes involved in metabolism of the dietary carcinogen 

effects 

in rats. Chem Biol 

2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine 

145: 251-265. 

Interact 

X Morris ME (2007) Diet/nutrition interactions with drug transporters. In: 

Wang 

transporters: Molecular characterization and role in drug disposition, 

Drug 

(eds G You and ME Morris), Wiley-Interscience pp665-708. 

RM, Harrison YE, Conney AH, Poppers PJ, Finster M (1968) Cigarette 

Welch 

Stimulatory effect on metabolism of 3,4-benzpyrene by enzymes in 

smoking: 

human placenta. Science 160: 541-542. 

RM, Harrison YE, Gommi BW, Poppers PJ, Finster M, Conney AH (1969) 

Welch 

effect of cigarette smoking on the hydroxylation of 3,4- 

Stimulatory 

and the N-demethylation of 3-methyl-4benzpyrene 

by enzymes in human placenta. Clin 

monomethylaminoazobenzene 

Pharmacol Ther 10: 100-109. 

O (2011) Interaction of phenothiazines, stilbenes and flavonoids with 

Wesołowska 

resistance-associated transporters, P-glycoprotein and MRP1. Acta 

multidrug 

Biochim Pol 58: 433-448. 

S Benowitz NL (1999) Drug interactions with tobacco smoking. An update. 

Zevin 

Pharmacokinet 36: 425-438. 

Clin

Figure Legends 

20 


Figure 1. Induction of hepatic aminoazo dye metabolism. In A, immature male 

rats were injected i.p. with 0.5 mg of 3-methylcholanthrene (3-MC) or corn oil 

(control vehicle) 24h before incubation of 3-methyl-4- 

monomethylaminoazobenzene (3-Me-MAB) with their liver homogenates for 12 min 

at 37°C, and 3-methyl-4-aminoazobenzene (3-Me-AB) was measured (Conney, 

1954). In B, immature male mice were injected i.p. with 2 mg of 3- 

methylcholanthrene or corn oil (control vehicle) once a day for one week. The data 

are expressed as μg of 3-Me-AB formed by 30 mg of liver in 20 min [Brown et al, 

1954]. In C, immature male rats were injected i.p. with 1 mg of 3-MC or corn oil 

(control vehicle), and the N-demethylation of 3-Me-MAB and reduction of 4- 

dimethylaminoazobenzene (DAB)was measured at different times after the injection 

[Conney et al, 1956]. 

Figure 2. Induction of hepatic benzo[a]pyrene (BP) and zoxazolamine 

metabolism. In A, immature male rats were injected i.p. with 0.1 or 1.0 mg of BP or 

corn oil (control vehicle) and sacrificed at various times after the injection [Conney 

et al, 1957]. In B, the rats were injected i.p. with 1 mg of BP or corn oil (control 

vehicle) and sacrificed 24 hr later [Conney et al, 1960]. In C, the rats were injected 

i.p. with 1 mg of BP or corn oil (control vehicle), and 24 hr later they were injected 

i.p. with zoxazolamine (100 mg/kg) and total body metabolism of zoxazolamine was 

measured [Conney et al, 1960].

21 


Figure 3. Effect of cigarette smoking and ingestion of charcoal-broiled beef on 

plasma levels of phenacetin in humans. In A, smokers and nonsmokers were 

given a 900 mg oral dose of phenacetin. Each value is the mean ± S.E. from 9 subjects 

[Pantuck et al, 1972; Pantuck et al, 1974a]. In B, a 900 mg oral dose of phenacetin 

was administered after a control diet for 7 days, a charcoal-broiled beef diet for 4 

days and a control diet for the next 7 days. Each value is the mean ± S.E. from 9 

subjects [Conney et al, 1976]. 

Figure 4. Plasma levels of nortriptyline in patients receiving 150mg daily 

(Asberg, 1974).

22 


Table 1. Concentrations of polycyclic aromatic hydrocarbons in cigarette 

smoke and charcoal-broiled beef 

Data obtained from Lijinsky et al, 1964 and Hoffmann et al, 1978.

23 


Table 2. Effects of cigarette smoking on the metabolism of xenobiotics by 

human placenta 

Each value is the mean ± S.E. The data was obtained from Welch et al, 1968; 

Welch et al, 1969; and Kapitulnik et al, 1976.

24 


Table 3. Representative polycyclic aromatic hydrocarbons in thirteen coffee 

brew samples 

*Data was obtained from Orecchio et al, 2009. 

**Induction of azo dye N-demethylase activity was measured at 24 hr 

after a single 1.86 μmol i.p. injection [Acros et al, 1961]. In another study, 

feeding 0.05% phenanthene in the diet to mice for one week stimulated 

azo dye N-demethylase activity [Brown et al, 1954]. 

*

Title Page Cigarette Smoking, Coffee Drinking, and Ingestion of ...

Create successful ePaper yourself

Delete template?

Save as template?