An enantiomeric interaction in the metabolism and tumorigenicity of (+)- and (-)-benzo[a]pyrene 7,8-oxide.

The (+)- and (-)-enantiomers of benzo[a]pyrene 7,8-oxide are hydrated stereospecifically at C-8 to (-)- and (+)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene, respectively, by rat hepatic epoxide hydrolase. The (-)-enantiomer of benzo[a]pyrene 7,8-oxide is metabolized by microsomal epoxide hydrolase at a rate 3- to 4-fold greater than the (+)-enantiomer. At low conversion of racemic substrate, however, benzo[a]pyrene 7,8-oxide is metabolized to the dihydrodiol at a rate equal to that of the (+)-enantiomer.

Antipyrine metabolism during the menstrual cycle.

Two studies were initiated to determine the effect of the menstrual cycle on antipyrine metabolism. In the first study a relatively large oral dose of antipyrine (15 mg/kg) was given on days, 3, 5, 10, 14, 16, 20, and 25 after the onset of menstruation. Salivary antipyrine half-lifes (t1/2S) declined progressively, suggesting that the long-term administration of this dose had stimulated antipyrine metabolism.

Mutagenicity and tumor-initiating activity of cyclopenta(c,d)pyrene and structurally related compounds.

The biological activities of benzo(a)pyrene, cyclopenta(c,d)pyrene, and 12 other structurally related compounds were assessed by mutagenicity studies with bacterial and mammalian cells and/or skin tumorigenicity studies with mice. The ability of the parent hydrocarbons to be metabolically activated to mutagenic products was examined in strains TA98 and TA100 of Salmonella typhimurium, using 3 experimental protocols. In each case, cyclopenta(c,d)pyrene was metabolically activated to products mutagenic to the bacteria to a greater extent than was benzo(a)pyrene.

Metabolism of benzo(e)pyrene by rat liver microsomal enzymes.

Metabolites of benzo(e)pyrene (B[e]P) formed upon incubation of [3H]-B[e]P with hepatic microsomes from control and induced rats have been separated by high-pressure liquid chromatography and identified by comparison of retention times, absorbance and fluorescence spectra with those of synthetic standards. The major metabolite produced was B[e]P-4,5-dihydrodiol, accounting for 20-30% of the total metabolism depending on the source of the microsomes. This was followed by a phenolic metabolite (shown not to be 4-OH-; 9-OH-; or 10-OH-B[e]P).

Tumorigenic activity of benzo(e)pyrene derivatives on mouse skin and in newborn mice.

The tumorigenic activities of benzo(e)pyrene and several of its derivatives were determined in two mouse tumor models. Newborn Swiss-Webster mice were given i.p.

Regulation of human drug metabolism by dietary factors.

Several dietary factors influence the oxidative metabolism of chemicals in humans. Increasing the ratio of protein to carbohydrate or fat in the diet, feeding cabbage and brussels sprouts or feeding charcoal-broiled beef for several days stimulates human drug metabolism. The chronic ingestion of ethanol stimulates drug metabolism whereas the chronic ingestion of methylxanthine-containing foods inhibits drug metabolism.

Absolute stereochemistry of the trans-dihydrodiols formed from benzo[a]anthracene by liver microsomes.

Through application of the exciton chirality method, absolute stereochemistry has been assigned to the (+)-and (-)-enantiomers of four of the five metabolically possible trans-dihydrodiols of the polycyclic hydrocarbon benzo[a]anthracene (BA). The (+)- and (-)-enantiomers of each of these dihydrodiols can be separated as their diastereomeric bis-esters with (-)-alpha-methoxy-alpha-trifluoromethylphenylacetic acid by high pressure liquid chromatography (HPLC). BA 3,4-, 5,6-, 8,9- and 10,11-dihydrodiol are formed in 38%, 36%, 78% and 66% enantiometric purity, respectively, by liver microsomes from phenobarbital-treated rats, whereas the liver microsomes from 3-methylcholanthrene(MC)-treated rats form BA 5,6-, 8,9- and 10,11-dihydrodiols with higher optical purity (62%, 96% and 96%, respectively).

Intraindividual variation in drug disposition.

Large interindividual differences occur in the in vivo metabolism of drugs due to genetic and environmental factors. Our studies show that intraindividual variabilities in rates of metabolism are relatively low for antipyrine and phenylbutazone, which are drugs that are primarily metabolized by the liver and have low hepatic extractions; whereas in the case of phenacetin, a drug that undergoes extensive metabolism in the gastrointestinal tract or during its first pass through the liver, or both, intraindividual variations in plasma half-lifes and areas under the plasma concentration-time curves are of much greater magnitude. In our studies, no effort was made to control the lifestyles of our subjects.

Differences in mutagenicity and cytotoxicity of (+)- and (-)-benzo[a]pyrene 4,5-oxide: a synergistic interaction of enantiomers.

In order to study the biological effects of (+)- and (-)-benzo[a]pyrene 4,5-oxide, a synthesis of these molecules has been developed based on the resolution of (+/-)-cis-4,5-dihydroxy-4,5-dihydrobenzo[a]pyrene. The (-) enantiomer of benzo[a]pyrene 4,5-oxide was 1.5- to 5.

Carcinogenicity of 2-hydroxybenzo(a)pyrene and 6-hydroxybenzo(a)pyrene in newborn mice.

Benzo(a)pyrene (BP), 2-hydroxybenzo(a)pyrene (2-HOBP), and 6-hydroxybenzo(a)pyrene (6-HOBP) were tested for tumorigenicity by i.p. injection into newborn mice.

Tumorigenicity of the diastereomeric benz[a]anthracene 3,4-diol-1,2-epoxides and the (+)- and (-)-enantiomers of benz[a]anthracene 3,4-dihydrodiol in newborn mice.

The tumorigenic activity of benz[a]anthracene (BA), the (+)- and (-)-enantiomers of trans-3,4-dihydroxy-3,4-dihydrobenz[a]anthracene (BA 3,4-dihydrodiol), and the racemic diastereomers of the BA 3,4-diol-1,2-epoxides [i.e., either or both of the diastereomeric 1,2-epoxides derived from BA 3,4-dihydrodiol in which the epoxide oxygen is cis (diol epoxide-1) or trans (diol epoxide-2) to the benzylic 4-hydroxyl group) was examined in newborn Swiss-Webster mice.

Stimulatory effect of phenobarbital on the metabolism of the oral contraceptive 17 alpha-ethynylestradiol-3-methyl ether (mestranol) by rat liver microsomes.

Pretreatment of rats with phenobarbital for 4 days stimulates the activity of liver microsomal enzymes that metabolize 17 alpha-ethynylestradiol-3-methyl ether (mestranol). This effect provides an explanation for the decreased uterotropic action of mestranol in rats pretreated with phenobarbital and may provide an explanation for unwanted pregnancies in women taking oral contraceptives in combination with phenobarbital or other enzyme-inducing drugs.