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

5
JPET #193193 PiP
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.