Studies on the hydroxylation of 3,4-benzpyrene by hepatic microsomes

Alvares, Alvito P.; Schilling, G.; Garbut, A.; Kuntzman, R.

doi:10.1016/0006-2952(70)90060-2

Cited by 57 publications

(10 citation statements)

References 6 publications

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“…As reported (30), the albumin significantly increased the rate and reproducibility of this assay. Samples were incubated at 370C under air in a shaking water bath.…”

Section: Methodssupporting

confidence: 53%

Induction of cytochrome CYPIA1 and formation of toxic metabolites of benzo[a]pyrene by rat aorta: a possible role in atherogenesis.

Thirman

Albrecht

Krueger

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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Cigarette smoking is a leading risk factor for atherosclerosis. Endothelial ijur may be the initial event in this process. The carcinogenic metabolites of the polycyclic aromatic hydrocarbons found in cigarette smoke tars could cause this injury. We tested this model by examining the effect of 3-methyicholanthrene adminisration on aortic polycyclic aromatic hydrocarbon metabolism. Immunoblotting with a monoclonal antibody (mAb 1-7-1) specific for cytochromes CYPIA1 and CYPIA2 showed that aortic microsomes from treated, but not from control, animals contained CYPIA1; the CYPIA1 was primarily in the endothelium. Aortic microsomes from induced animals metabolized benzo[alpyrene (BaP) to the 7R,8S,9,10-tetrahydrotetrol-, 7,8-dhydrodiol-, 1,6 quinone-, 3,6 quinone-, 6,12 quinone-, 3-hydroxy-, and 9-hydroxy-BaP. mAb 1-7-1 inhibited the formation of the tetrahydrotetrol, the dihydrodiol-BaP, and the 3-hydroxy-BaP but did not inhibit the quinones or the 9-hydroxy-BaP. Arachidonic acid did not affect metabolism. These data suggest that the aortas of induced animals metabolize the BaP in cigarette smoke to carcinogenic and toxic products and that this metabolism may initiate vessel injury and lead to the accelerated atherosclerosis seen in cigarette smokers.Atherosclerotic vascular disease is the leading cause of death in developed nations. This process may be initiated by endothelial injury, which leads to the formation of a nidus for mononuclear cellular infiltration, cholesterol deposition, and platelet aggregation (1). Cardio-and cerebral vascular events are more frequent in individuals with hypertension, hyperlipidemia, and diabetes mellitus and in smokers. There has been some question of whether the increased incidence of vascular events seen in smokers is due to increased atherosclerosis or to alterations in other systems, such as the coagulation pathways. Although the latter may be important, the preponderance of evidence suggests that smokers have a significant increase in the incidence and degree of atherosclerosis in both the coronary and peripheral arteries (2).It is unclear which of the toxic products in the smokecarbon monoxide (3), nicotine (4), or the tars-are responsible for this acceleration. The tars, which include the polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (BaP), are possible candidates (5). Although BaP is not toxic, it is metabolically activated to highly toxic, mutagenic, and carcinogenic products-such as various epoxides and quinones. These toxic metabolites, if formed in the vessel wall, could initiate atherosclerosis by injuring the endothelial and muscle cells. If such is the case, then the arterial wall should catalyze their formation because it is unlikely that they could be transported to the peripheral vessels from the liver or lungs. Previous workers have found that a specific cytochrome P450, CYPIA1, catalyzes this metabolism in other organs (6, 7). In smooth muscle cells of young animals CYPIA1 is a constitutive form (8), but in older animals it is found in many or...

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“…As reported (30), the albumin significantly increased the rate and reproducibility of this assay. Samples were incubated at 370C under air in a shaking water bath.…”

Section: Methodssupporting

confidence: 53%

Induction of cytochrome CYPIA1 and formation of toxic metabolites of benzo[a]pyrene by rat aorta: a possible role in atherogenesis.

Thirman

Albrecht

Krueger

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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“…Spectral measurements have demonstrated that the apparent dissociation constant for cyclohexane binding is a function of cytochrome P-450.concentration [ 11. The rate of benzpyrene hydroxylation catalysed by cytochrome P-450 is non-linear with enzyme concentration except at very low enzyme concentrations [2]. Imipramine metabolism studies give KM values that are a function of protein concentra.…”

Section: Introductionmentioning

confidence: 99%

Ligand partitioning into membranes: Its significance in determining K_M and K_S values for cytochrome P‐450 and other membrane bound receptors and enzymes

1976

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“…The mixture was incubated at 370 for 5 min and the product was measured by the method of Nebert and Gelboin (21). In the benzo-[alpyrene hydroxylase assay, 9000 X g supernatant was used because previous studies (22) had shown that the Michaelis constant was similar whether 9000 X g supernatant or microsomes were used. Cytochrome P450 content was determined by the method of Omura and Sato (23), from the CO-difference spectrum of dithionite-reduced microsomes, using an extinction coefficient of 91 mM-1 cm-' between 450 or 448 and 490 nm.…”

mentioning

confidence: 99%

Polychlorinated Biphenyls: A New Type of Inducer of Cytochrome P-448 in the Liver

Alvares

Bickers

Kappas

1973

Proc. Natl. Acad. Sci. U.S.A.

188

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The CO-difference spectrum of microsomes from rats treated with the polychlorinated biphenyls mixture, Aroclor 1254, has an absorption maximum at 448 nm. With ethylisocyananide as the ligand for reduced microsomes, Aroclor 1254 treatment causes a shift in the 455-nm peak to 453 nm and increases the ratio of absorbance of 455 nm to that at 430 nm from 0.53, obtained with untreated rats, to 1.24. These findings are similar to those seen in rats treated with the polycyclic hydrocarbon, 3-methylcholanthrene, but differ from those that characterize cytochrome P-450 in control or phenobarbitaltreated rats. Aroclor 1254 treatment results in a tripling of cytochrome P-448 content and a 10-fold increase in benzo-[alpyrene hydroxylation. However-unlike 3-methylcholanthrene, but like the phenobarbital type of inducing agents-Aroclor 1254 treatment causes a significant enhancement of ethylmorphine N-demethylase. These data suggest that Aroclor 1254-induced cytochrome P-448 may be catalytically different from the 3-methylcholanthreneinduced P-448 or that the hemoprotein(s) induced by Aroclor 1254 may be a mixture of cytochromes P-448 and P-450 exhibiting catalytic properties of both cytochromes.

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Studies on the hydroxylation of 3,4-benzpyrene by hepatic microsomes

Cited by 57 publications

References 6 publications

Induction of cytochrome CYPIA1 and formation of toxic metabolites of benzo[a]pyrene by rat aorta: a possible role in atherogenesis.

Induction of cytochrome CYPIA1 and formation of toxic metabolites of benzo[a]pyrene by rat aorta: a possible role in atherogenesis.

Ligand partitioning into membranes: Its significance in determining K_M and K_S values for cytochrome P‐450 and other membrane bound receptors and enzymes

Polychlorinated Biphenyls: A New Type of Inducer of Cytochrome P-448 in the Liver

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Studies on the hydroxylation of 3,4-benzpyrene by hepatic microsomes

Cited by 57 publications

References 6 publications

Induction of cytochrome CYPIA1 and formation of toxic metabolites of benzo[a]pyrene by rat aorta: a possible role in atherogenesis.

Induction of cytochrome CYPIA1 and formation of toxic metabolites of benzo[a]pyrene by rat aorta: a possible role in atherogenesis.

Ligand partitioning into membranes: Its significance in determining KM and KS values for cytochrome P‐450 and other membrane bound receptors and enzymes

Polychlorinated Biphenyls: A New Type of Inducer of Cytochrome P-448 in the Liver

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Ligand partitioning into membranes: Its significance in determining K_M and K_S values for cytochrome P‐450 and other membrane bound receptors and enzymes