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PubMed1983

Effect of chrysotile asbestos and silica on the microsomal metabolism of benzo(a)pyrene.

The effects of chrysotile, water-leached chrysotile, and silica on microsomal metabolism of benzo(a)pyrene in vitro were studied. Examination of benzo(a)pyrene metabolites generated by 3-methylcholanthrene-pretreated rat liver microsomes, in the presence of chrysotile fibers, revealed a reduction in the overall metabolism of the hydrocarbon. Thus, chrysotile appeared to modify the activities of aryl hydrocarbon hydroxylase and epoxide hydrolase. Leaching chrysotile in deionized water for 24 hr elicited a similar response. Silica, in contrast to chrysotile, did not decrease the microsomal metabolism of benzo(a)pyrene. Chrysotile, as well as water-leached chrysotile, considerably diminished the microsomal production of water-soluble benzo(a)pyrene metabolites. Precoating the fibers with heparin or bovine serum albumin partially abolished this inhibition. The liver microsomal metabolism of benzo(a)pyrene in rats subjected to intraperitoneal administration of chrysotile was 58% of that in untreated rats.

Animals↗
PubMed1979

Oxidative biotransformation of benzo(a)pyrene by human lung microsomal fractions prepared from surgical specimens.

1. Microsomal fractions were prepared from 15--50 g specimens of human lung tissue (mostly alveolar) obtained at surgical resections of 13 middle-aged male patients suffering from different pulmonary tumours. Marker enzyme assays indicated that the frations contained about 25% of the endoplasmic reticulum of the homogenate and about 10% of its mitochondrial membranes. 2. The content of cytochrome b5 corresponded to that of rodent lung microsomes, whereas the apparent content of cytochrom P-450 was much lower. 3. The extent of benzo(a)pyrene metabolism varied 13-fold between individuals in the group and was not detectable in about 40% of the cases. 4. The dihydrodiols as % of total metabolites formed was higher than in laboratory animals, the 7,8-dihydrodiol in most cases amounting to more than 40% of total dihydrodiols. 5. The apparent rate of hydroxylation was stimulated by 1 mM 2-diethylaminothyl 2,2-diphenylvalerate and by 1 mM 1,2-oxy-3,3,3-trichloropropane, but inhibited moderately by 0.1 mM metyrapone and extensively by 0.05 mM 7,8-benzoflavone. 6. Ethoxyresorufin deethylation qualitatively paralleled benzo(a)pyrene hydroxylation among individuals.

Benzopyrene Hydroxylase↗
PubMed1981

Differential effect of several inducers on hepatic and mammary benzo(A)pyrene metabolism in rat and hamster.

Rat and hamster mammary gland, in comparison with the liver, were examined for their in vitro ability to metabolize polycyclic aromatic hydrocarbons, and for the effects of pretreatment with various mixed function oxidase inducers on this metabolism. Hamster mammary microsomal benzo(a)pyrene (BP) hydroxylase activity was 4-fold greater than that in the rat, and this activity was induced 3- to 5-fold in the hamster, and 7- to 13-fold in the rat, by pretreatment with 7,12-dimethylbenz(a)anthracene, beta-naphthoflavone, Aroclor 1254 or 3-methylcholanthrene. Hamster hepatic microsomal BP-hydroxylase activity was 80-fold greater than in the rat. Whereas pretreatment with these enzyme inducers enhanced rat hepatic activity by 20- to 30-fold, little effect of "inducers" was observed on the hamster hepatic enzyme, even when the formation of the various BP metabolites was determined by high pressure liquid chromatography.

Animals↗
PubMed1975

Inhibition of benzo(alpha)pyrene metabolism catalyzed by mouse and hamster lung microsomes.

Induced and constitutive microsomal enzymes of mouse and hamster lungs catalyze both the hydroxylation of benzo(alpha)pyrene and reactions that lead to its irreversible binding to macromolecules. For mouse and hamster, the induced lung hydroxylases have Km values of 1.10 and 0.52 muM, respectively. The induced hydroxylases are strongly inhibited by 7,8-benzoflavone and are stimulated by cyclohexene oxide, an inhibitor of epoxide hydrase. Formation of the macromolecular product by the induced "binding" enzyme follows. Michaelis-Menten kinetics, except for substrate inhibition, and has Km values of 0.52 and 0.25 muM for lung microsomes from mouse and hamster, respectively. These reactions are also inhibited by 7,8-benzoflavone. The reaction catalyzed by the constitutive hydroxylase of mouse lungs is characterized by a brief lag period but proceeds in a linear fashion after the lag. The enzyme requires 60 muM benzo(alpha)pyrene to achieve maximum reaction velocity. Above this concentration, strong substrate inhibition is observed; accurate values for Vmax and Km cannot be derived. The constitutive hydroxylases are moderately inhibited by butylated hydroxytoluene, retinol, cyclohexene oxide, and 7,8-benzoflavone. The product of the constitutive "binding" enzyme is formed in a reaction that follows Michaelis-Menten kinetics. The Km value for enzymes from mouse and hamster lungs are 11.8 and 4.9 muM, respectively. Formation of this product is strongly inhibited by butylated hydroxytoluene and by retinol but not strongly by 7,8-benzoflavone or cyclohexene oxide. Since other evidence indicates that a constitutive enzyme may be involved in carcinogenesis by benzo(alpha)pyrene and since this reaction is inhibited by two known anticarcinogens, we suggest that it may be involved in this process.

Animals↗
PubMed1975

[Studies on the metabolism of benzo(a)pyren in alveolar-macrophages. I. Uptake of benzo(a)pyrene and induction of benzo(a)pyrene hydroxylase (author's transl)].

Alveolar macrophages play a significant role in the elimination of inhaled foreign compounds and particles from the lung. The question arises, if alveolar macrophages participate in the detoxification or activation of environmental carcinogenic compounds. In the first communication on this subject we describe experiments concerning the uptake of benzo(a)pyrene and the activity of the metobolizing enzymes. The alveolar macrophages are obtained by lung lavage from guinea pigs (Fig. 1,2,3). The cells are grown in monolayers in petri dishes or on the surface of cover slips or glass-vials. The uptake of benzo(a)pyrene in alveolar macrophages is measured by a microfluorimetric method in single cells and by using labelled substrate. The results obtained by both methods indicate that the uptake is terminated between 1-2 h (Fig. 4, 5). The kinetics of uptake and elimination (Fig. 8, 9). are influenced by the concentration of serum (Fig. 6) and benzo(a) pyrene (Fig. 7) in the medium. Two mechanism for the uptake in the alveolar macrophages are discussed: diffusion and pinocytose. The activity of the metabolizing enzymes (benzo(a)pyrene hydroxylase, aryl hydrocarbon hydroxylase)increases during incubation with benzo(a)pyrene (Fig. 10, 11) and is dependant on the concentration of benzo(a)pyrene in the growth medium (Fig. 12). The enzyme activity is inducible also by other polycyclic hydrocarbons (Tab. 1). The induction is inhibited by actinomycin D and cycloheximid (Tab. 2). The activity of the enzymes in guinea pig alveolar macrophages is comparable to the activity in leucocytes and alveolar-macrophages from humans (Tab. 3, 4).

Animals↗
PubMed1975

Genetic differences in the induction of aryl hydrocarbon hydroxylase and benzo(a)pyrene carcinogenesis in C3H/He and DBA/2 strains of mice.

The effects of 3-methylcholanthrene and 5,6- and 7,8-benzoflavones on aryl hydrocarbon (benzo[a]pyrene) hydroxylase in the liver, small intestine, lung, and skin tissues from C3H/He and DBA/2 strains of mice under the controlled lighting conditions were examined. Apparent differences were observed in the inducibility of the hepatic enzyme by the inducers between the two strains of mice, showing that the enzyme in the C3H/He mice is inducible but not in the DBA/2 mice. Comparison of the results on the enzyme induction by 3-methylcholanthrene in the liver among the parent, intercrossed, and backcrossed mice suggested that the inducibility may be inherited as a single autosomal dominant trait. However, different genetic responses to 3-methylcholanthrene and benzoflavones in the enzyme of small intestine might be considered, because a discrepancy in the inducibility of the enzyme between the liver and the small intestine from the identical mice was demonstrated when the progeny of F2 and (DBA/2 times F1) backcross were used. On the other hand, no apparent difference was found in the inducibility of the enzyme in the lung and skin between the C3H/He and the DBA/2 mice. It is assumed that the genetic regulation of the induction of aryl hydrocarbon hydroxylase was separately controlled in the respective tissues from the identical mice. By the repeated topical applications of benzo[a]pyrene, the incidence of skin cancer was higher in the DBA/2 mice than in the C3H/He mice. The relationship between the induction of aryl hydrocarbon hydroxylase and carcinogenicity in the skin is briefly discussed.

Animals↗
PubMedDate not supplied

Xenobiotic metabolism and enzyme induction in isolated rat intestinal microsomes.

Intestinal microsomes were isolated from rats pretreated with 3-methylcholanthrene (MC), phenobarbital (PB), and pregnenolone-16alpha-carbonitrile (PCN). The metabolism of benzo[a]pyrene (BP), 7-ethoxyresorufin, 7-ethoxycoumarin, and biphenyl were examined. MC induces a 30-fold increase in BP metabolism. With control microsomes, BP metabolism is inhibited by metyrapone, SKF 525-A, and antimycin A, but is stimulated 4.5-fold by rotenone. With microsomes from MC-treated rats, BP metabolism is inhibited by metyrapone, SKF 525-A, antimycin A, and rotenone. MC pretreatment increases 7-ethoxyresorufin de-ethylase by almost 20-fold and ethoxycoumarin de-ethylase by almost 18 fold. PB pretreatment produces less than a 2-fold increase in both de-ethylases. PCN pretreatment inhibits 7-ethoxyresorufin and 7-ethoxycoumarin de-ethylases. In rats fasted for 2 days, neither de-ethylase could be detected in intestinal microsomes. Biphenyl 2- and 4-hydroxylase activities were induced less than 4-fold by MC or PB pretreatment.

Animals↗