Diminution in kerosene-mediated induction of drug metabolizing enzymes by asbestos in rat lungs.

In order to determine the pulmonary toxicity of kerosene and its ignition product (soot) in asbestos exposed subjects, the activities of phase I and phase II drug metabolizing enzymes in rat lungs after single intratracheal co-exposure to Indian chrysotile asbestos and kerosene or its soot and Indian chrysotile were assayed. Exposure to kerosene or its soot resulted in a significant increase in the level of microsomal cytochrome P-450 and the activity of P-450 dependent monooxygenase, benzo(a)pyrene hydroxylase, as well as in the activities of microsomal epoxide hydrase and cytosolic glutathione-S-transferase (GST). However, in chrysotile exposed animals a reverse pattern in these parameters was recorded. The co-exposure to chrysotile and kerosene or chrysotile and soot led to a significant depletion in cytochrome P-450 level and a decrease in the activities of benzo(a)pyrene hydroxylase, epoxide hydrase and GST when compared to kerosene and soot controls, respectively. These results suggest that asbestos by altering the pulmonary drug metabolizing enzyme system may increase the toxic potential of kerosene and its ignition product in the respiratory system.     

Action of styrene and its metabolites styrene oxide and styrene glycol on activities of xenobiotic biotransformation enzymes in rat liver in vivo

The effects of the administration of styrene and its metabolites, styrene oxide and styrene glycol, on drug metabolizing enzymes of rat liver were studied. Styrene (three or six daily doses of 500 g/kg) doubled the activities of microsomal p-nitroanisole O-demethylase, epoxide hydrase (styrene oxide as substrate), and UDP glucuronosyltransferase (p-nitrophenol) when measured in microsomes pretreated in vitro with digitonin or trypsin. On the other hand, glycine conjugation, the cytochrome P-450 content, and activities of NADPH cytochrome c reductase and benzpyrene hydroxylase, were less affected by styrene. Styrene oxide was more toxic to rats than styrene or styrene glycol and it also caused (one dose of 375 mg/kg) a significant decrease in the activities of benzpyrene hydroxylase and p-nitroanisole O-demethylase and in the cytochrome P-450 content. Epoxide hydratase NADPH cytochrome c reductase, and UDP glucuronosyltransferase were more resistant towards styrene oxide. Styrene glycol did not significantly alter the activities of drug metabolizing enzymes. The current data show that styrene causes an increase in the activities of some enzymes involved in its own metabolism.     

2,2-Dimethyl-5-t-butyl-1,3-benzodioxole: an unusual inducer of microsomal enzymes

Our previous studies have shown that 2,2-dimethyl-5-t-butyl-1,3-benzodioxole (DBBD), a methylenedioxyphenyl (MDP) analog in which the methylene hydrogens have been replaced by methyl groups, does not form an inhibitory complex with cytochrome P-450 nor induce this cytochrome. However, in the present experiments, DBBD-treated male Dub:ICR mice showed an increase in NADPH-dependent cytochrome c (P-450) reductase and epoxide hydrolase activity. This separation of cytochrome P-450 induction from the induction of epoxide hydrolase and NADPH-dependent cytochrome c (P-450) reductase appears to be unique among inducers of xenobiotic metabolizing enzymes. In similar experiments, mice were treated with phenobarbital + DBBD or 3-methylcholanthrene + DBBD and the following parameters were measured: cytochrome P-450 content; NADPH-dependent reduction of cytochrome c; ethylmorphine and benzphetamine N-demethylase; 7-ethoxycoumarin O-deethylase; benzo[a]pyrene hydroxylase; and ethoxyresorufin O-deethylase. The microsomal proteins were examined by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (SDS-PAGE). Phenobarbital + DBBD treatment gave results which did not differ significantly from those obtained with phenobarbital alone. In contrast, cytochrome P-450 content and benzo[a]pyrene hydroxylase and ethoxyresorufin O-deethylase activities were less in mice treated with 3-methylcholanthrene + DBBD than in animals treated with 3-methylcholanthrene alone. SDS-PAGE confirmed that induction of cytochrome P-450 by 3-methylcholanthrene was reduced by DBBD, suggesting that the latter compound may be an antagonist to the Ah cytosolic receptor.     

Regio-Selectivity of Purified Forms of Rabbit Liver Microsomal Cytochrome P-450 in the Metabolism of Benzo(a)pyrene,n-Hexane and 7-Ethoxyresorufin

Abstract: The specificity of electrophoretically homogeneous preparations of rabbit liver microsomal cytochrome P-450lm _2–4 towards oxygenation of n-hexane, 7-ethoxyresorufin and benzo(a)pyrene was examined using a reconstituted system consisting of cytochrome P-450, NADPH-cytochrome P-450 reductase and dilauroylphosphatidylcholine. Epoxide hydrase was included when benzo(a)pyrene was used as substrate. Cytochrome P-450lm ₂ was most active in n-hexane and benzo(a)pyrene oxygenation especially with regard to the formation of 2-hexanol, B(a)P-4,5-dihydrodiol and B(a)P-phenol metabolites. 7-Ethoxyresorufin was, however, a very poor substrate for cytochrome P-450lm ₂. Cytochrome P-450lm ₃ had less activity towards the investigated substrates while cytochrome P-450lm ₄ preferentially formed 2- and 3-hexanol, resorufin and B(a)P-9,10-dihydrodiol. Cytochrome P-450lm ₄ isolated after pretreatment with 3-methylcholanthrene or pheno-barbital showed roughly the same characteristics except in the formation of 1-hexanol where cytochrome P-450lm ₄ isolated after phenobarbital treatment was the most effective. The formation of B(a)P-4,5- and ?9,10-dihydrodiols was greatly increased by incorporation of epoxide hydrase. Our results indicate a certain specificity of the different forms of cytochrome P-450 in the liver microsomes although some overlap in activities was observed.     

Protective role of ascorbic acid against asbestos induced toxicity in rat lung: in vitro study

Asbestos fibers adsorb cytochrome P-450 and P-448 proteins from rat lung micosomal fractions and liberate heme from cytochrome P-448 on prolonged incubation in vitro. further, fibers, decrease the activities of benzo(a)pyrene hydroxylase and glutathione-S-transferase in microsomal and cytosolic fractions respectively. Mineral fibers also stimulate both the enzymatic (NADPH-induced) and non-enzymatic (Fe2(+)-induced) lipid peroxidation in microsomal fractions. Preincubation of microsomal and cytosolic fractions with a physiological concentration of ascorbic acid ameliorates, to a large extent, the changes induced by asbestos fibers.     

Induction of hepatic cytochrome P-450c-dependent monooxygenase activities by dantrolene in rat

The effect of dantrolene sodium, a skeletal muscle relaxant, on drug metabolizing enzymes has been investigated after treatment of rats with a dose of 200 mg/kg for five days. We observed an induction of cytochrome P-450c and epoxide hydrolase in immunoassays and activities. An enhancement of the UDP-glucuronosyltransferase (GT1) activity was observed. We also reported a decrease of both liver cytochrome P-450 content and microsomal cytochrome P-450b dependent N-demethylation activities. On the other hand, the binding of dantrolene on microsomal cytochrome P-450 produced a type I difference spectrum, these data were obtained with liver microsomal cytochrome P-450c induced by 3-methylcholanthrene.     

Protective Role of Ascorbic Acid Against Asbestos Induced Toxicity in Rat Lung: In Vitro Study

ABSTRACT

Asbestos fibers adsorb cytochrome P-450 and P-448 proteins from rat lung micosomal fractions and liberate heme from cytochrome P-448 on prolonged incubation in vitro. further, fibers, decrease the activities of benzo(a)pyrene hydroxylase and glutathione-S-transferase in microsomal and cytosolic fractions respectively. Mineral fibers also stimulate both the enzymatic (NADPH-induced) and non-enzymatic (Fe²⁺ -induced) lipid peroxidation in microsomal fractions. Preincubation of microsomal and cytosolic fractions with a physiological concentration of ascorbic acid ameliorates, to a large extent, the changes induced by asbestos fibers.     

Enhancement of microsomal monooxygenase,epoxide hydrase and udpglucuronyltransferase by aldrin,dieldrin and isosafrole administrations in rat liver

The effects of intraperitoneal administration of aldrin (10 mg/kg), dieldrin (10 mg/kg) and isosafrole (50 mg/kg) were investigated on the activities of drug biotransformation enzymes in rat liver. All the compounds studied were found to enhance the activities of microsomal monooxygenase (e.g. p-nitroanisoleO-demethylase, aryl hydrocarbon hydroxylase), epoxide hydrase (styrene oxide as substrate) and UDPglucuronyltransferase (p-nitrophenol as aglycone). Dieldrin, the epoxidized derivative of aldrin, was a more potent inducer than the parent compound itself. NADPH cytochrome c reductase activity was enhanced 2.5-fold, p-nitroanisole O-demethylase 7-fold, benzopyrene hydroxylase 2-fold, and epoxide hydrase 5-fold after treating rats with dieldrin for 6 days. The increase in activity of the microsomal UDPglucuronyltransferase could be only detected after an in vitro digitonin treatment of microsomal membranes, the enhancement being about 1.5-fold after administering dieldrin for 6 days.The administration of isosafrole to rats increased especially p-nitroanisoleO-demethylase activity in liver microsomes (10-fold in 3 days). NADPH cytochrome c reductase activity was increased 2-fold, cytochrome P-450 content 1.2-fold, benzpyrene hydroxylase activity 2.5-fold and epoxide hydrase activity 1.2-fold after treatment of rats for 3 days. UDPglucuronyltransferase activity increased 2.2-fold by treating rats for 6 dyas with isosafrole. This increase was, however, only to be seen in in vitro digitonin-activated microsomes due to the latency of UDPglucoronyltransferase.     

In vivo effects of nitrogen dioxide and ozone on xenobiotic metabolizing systems of rat lungs

Male Jcl:Wistar rats were exposed continuously to either ozone (O3) or nitrogen dioxide (NO2) for 7 and 14 days to examine the effects of these gases on the xenobiotic metabolizing systems of lung microsomes. Exposure to 0.2 and 0.4 ppm O3 increased NADPH-cytochrome P-450 reductase activity and cytochrome P-450 as well as microsomal protein by the 14th day, whereas NADH-cytochrome b5 reductase was not affected. The most marked increase was observed in cytochrome P-450. In parallel to this increment, the activities of benzo(a)pyrene hydroxylase and 7-ethoxycoumarin O-deethylase of exposed animals increased significantly on the 7th and 14th days of exposure to 0.2 and 0.4 ppm 03. In contrast, exposure to 1.2 and 4 ppm NO2 decreased cytochrome P-450 on the 7th day. Moreover, the 7-ethoxycoumarin O-deethylase activity in exposed animals decreased to 61% (P less than 0.05) and 74% (P less than 0.001) of control on the 7th and 14th days of exposure to 4 ppm NO2, respectively. This decrease occurred in a dose-dependent manner with exposure to 0.4-4.0 ppm NO2, whilst benzo(a)pyrene hydroxylase activity was not affected. These results show that O3 at low doses induces xenobiotic metabolizing activities in the lung, whereas NO2 reduces this.     

Changes in the rat liver drug metabolizing system during a short thiobenzamide feeding cycle

The changes in the hepatic drug metabolizing enzymes induced by the liver tumor promoter thiobenzamide (TB) were investigated. Feeding of TB to rats at a promoting regimen (1 g/kg of diet for 2 weeks) resulted in a significant decrease in the amount of liver microsomal cytochrome P-450 and of total heme. Also, the activity of cytochrome P-450 dependent monooxygenases (aminopyrine demethylase, arylhydrocarbonmonooxygenase and ethoxycoumarindeethylase) and FAD-containing monooxygenase (N,N-dimethylaniline N-oxidase and TB S-oxidase) were depressed. By contrast, phase II enzymes such as epoxide hydrase, UDP-glucuronyl transferase and GSH-transferase were significantly induced. This overall change in the drug metabolizing system was associated with tolerance of the liver towards a high necrogenic dose of TB itself as well as with an increase of mitoses and apoptosis of the hepatocytes. The findings suggest a possible relationship between this TB-induced adaptive response and the promoting activity of the compound on liver carcinogenesis.     

Xenobiotic metabolizing enzymes are not restricted to parenchymal cells in rat liver

To characterize the distribution and inducibility of drug metabolizing enzymes within different hepatic cell populations, the activities of aminopyrine N-demethylase, ethoxyresorufin O-deethylase, microsomal epoxide hydrolase and cytosolic glutathione transferase were measured in liver parenchymal, Kupffer, and endothelial cells isolated from untreated rats or rats pretreated with phenobarbital, 3-methylcholanthrene, or Aroclor 1254. Enzyme activities, measurable in all cases, were 2.3- to 5.7-fold higher in parenchymal cells than in Kupffer and endothelial cells. Phenobarbital increased aminopyrine N-demethylase, microsomal epoxide hydrolase, and cytosolic glutathione transferase activities, whereas 3-methylcholanthrene enhanced ethoxyresorufin O-deethylase, epoxide hydrolase, and glutathione transferase activities in the three cell populations. Aroclor 1254 consistently induced each of the enzyme activities in parenchymal, Kupffer, and endothelial cells. Western blot analyses revealed clear differences in the expression of proteins immunologically related to cytochrome P-450 PB-1, and glutathione transferases B and X in parenchymal cells compared with the corresponding Kupffer and endothelial cells. In contrast, only minor differences between the cell types were apparent in the expression of cytochromes P-450 PB-4, P-450 MC1a, P-450 MC1b and microsomal epoxide hydrolase. These studies establish that oxidative and postoxidative drug metabolizing enzymes are not restricted to parenchymal cells: similar but distinguishable complements of these enzymes are also found in Kupffer and endothelial cells.     

Comparison of monooxygenase activities and cytochrome P-450 isozyme concentrations in human liver microsomes

Concentrations of three human liver microsomal cytochrome P-450 isozymes and 20 different monooxygenase activities were determined in human liver microsomal preparations. The results of correlation analysis suggest that: there are important variations in the amounts of the three cytochrome P-450 isozymes measured, particularly P-450(8) and P-450(9); aldrin epoxidase, d-benzphetamine N-demethylase, and S-warfarin 4-hydroxylase activities are linked to cytochrome P-450(5); aryl hydrocarbon (benzo(a)pyrene) hydroxylase and 4-nitroanisole-O-demethylase activities are linked to P-450(8); hydroxylations at the 4'-, 6-, 7-, and 8-positions of R-warfarin are closely linked to each other but are not correlated with other measured monooxygenase activities or P-450 isozyme levels; and P-450(9) is not related to any of the catalytic activities tested. Thus, certain monooxygenase activities can be attributed to specific cytochrome P-450 isozymes. This approach should be useful in suggesting the roles of different cytochromes P-450 in drug metabolism in man which can be further examined using in vitro and in vivo methods.     

Regulation of hepatic monooxygenases by phenobarbital, 3-methylcholanthrene, and polychlorinated biphenyls in rapid and slow acetylator mice

A/J and C57BL/6J inbred mouse strains have been previously used as models of slow and fast acetylators, respectively, of human acetylator polymorphism. Studies were carried out to characterize possible differences in basal activities of hepatic monooxygenases and the response of these mouse strains to microsomal enzyme inducers. No significant difference in cytochrome P-450 content and associated enzyme activities of ethylmorphine N-demethylase and benzo(a)pyrene hydroxylase were observed between the two strains. The administration of the inducers, phenobarbital or the polychlorinated biphenyl mixture Aroclor 1254, resulted in significant increases in cytochrome P-450 and ethylmorphine N-demethylase activity and minimal changes in benzo(a)pyrene hydroxylase activity in both strains. Pretreatment with 3-methylcholanthrene resulted in little or no increase in N-demethylase activity in both strains. The polycyclic hydrocarbon caused a CO difference spectral shift to a lower wavelength only in the C57BL/6J mice. Further, it increased benzo(a)pyrene hydroxylase activity in both strains, but to a greater extent in the C57BL/6J strain. Electrophoretic studies using solubilized microsomal preparations confirmed the findings that the fast acetylators were highly responsive to the inducing properties of the polycyclic aromatic hydrocarbon, whereas the slow acetylators were relatively much less responsive to its inducing properties. The latter strain appeared to be more responsive to the inducing properties of the phenobarbital class of inducers, as reflected in the inducibility of cytochrome P-450 and the associated enzymic activities in the liver.     

Kerosene soot genotoxicity: enhanced effect upon co-exposure with chrysotile asbestos in Syrian hamster embryo fibroblasts

Epidemiological and experimental studies have suggested an enhancement of asbestos-induced bronchogenic carcinoma by cigarette smoke. Further, our recent experimental and epidemiological studies have indicated that besides smoking, several other compounds including kerosene soot may accelerate disease processes in asbestos-exposed animals as well as in the humans. Incomplete combustion of kerosene oil generates large volumes of soot, which contains various polycyclic aromatic hydrocarbons and aliphatic compounds. As reported earlier, exposure to kerosene soot is known to cause biochemical and pathological changes in the pulmonary tissue, which may cause cardiopulmonary disorders. In this study we investigated genotoxic effects caused by kerosene soot and chrysotile asbestos as well as co-exposure of kerosene soot and chrysotile using Syrian hamster embryo fibroblasts (SHE). The micronucleus assay revealed a significant increase of induced micronuclei (MN), (P相似文献   

Effect of pyrrolizidine alkaloids from tansy ragwort (Senecio jacobaea) on hepatic drug-metabolizing enzymes in male rats

Ad lib. consumption of diets containing 5% tansy ragwort (Senecio jacobaea) for 1–4 weeks produced a 5- to 6-fold increase in hepatic microsomal epoxide hydrase and significant increases in cytosolic glutathione S-transferase activities in male Long-Evans rats. An enhancement of these enzyme activities was also observed when a diet containing 1% tansy ragwort was fed for a period of 3 weeks. Feeding a diet containing 0.5% pyrrolizidine alkaloid (PA) mixture extracted from tansy ragwort for 1 week produced a 5-fold increase in hepatic epoxide hydrase and a 73 per cent increase in glutathione S-transferase activities. In contrast, hepatic microsomal aryl hydrocarbon hydroxylase activity (AHH) was reduced significantly by feeding diets containing 5% tansy ragwort or a 0.5% alkaloid mixture. Hepatic microsomal cytochrome P-450 content was lowered following consumption of the 0.5% alkaloid mixture but not by feeding a 5% tansy ragwort diet, the difference presumably being a result of the lowered PA intake by the latter animals. Exposure to the pyrrolizidine alkaloids, therefore, may influence significantly the capacity of animals to metabolize endogenous or foreign compounds and possibly also affect the subsequent biotransformation and toxicity of these plant constituents.     

Isopropanol enhancement of cytochrome P-450-dependent monooxygenase activities and its effects on carbon tetrachloride intoxication

Acute or chronic treatment of rats with isopropanol caused a significant increase in hepatic cytochrome P-450 content and a two- to threefold increase in aniline hydroxylase and 7-ethoxycoumarin O-deethylase activities, but no significant change in ethylmorphine N-demethylase or benzo(a)pyrene hydroxylase activity. In rats treated with isopropanol and challenged with CCl4, liver toxicity of CCl4 was characteristically potentiated, as assessed by elevation of serum glutamic-pyruvic transaminase (SGPT) levels. Isopropanol pretreatment also potentiated CCl4-induced damage to the hepatic monooxygenase system. In addition to a decrease in cytochrome P-450, rats treated with isopropanol and challenged with CCl4 showed a nonspecific decrease not only in aniline hydroxylase and 7-ethoxycoumarin O-deethylase activities, but also in ethylmorphine N-demethylase, benzo(a)pyrene hydroxylase, and NADPH-cytochrome c reductase activities. These results were confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of solubilized microsomes. The electrophoretic results showed that isopropanol pretreatment markedly potentiated the CCl4-caused destruction of cytochrome P-450 hemeproteins. The data strongly suggest that isopropanol increases one or more forms of cytochrome P-450 which selectively enhance the metabolism of CCl4 to an active metabolite. This active metabolite then causes a nonselective damage to the microsomal mixed-function oxidase system.     

培氟沙星对大鼠肝微粒体酶系的抑制作用

大鼠经培氟沙星４００ｍｇ／ｋｇ，ｉｇ，ｑｄ×７ｄ后，肝微粒体酶系中的细胞色素ｂ５、氢基比林－Ｎ－脱甲基醉，７－乙氧基香豆素－Ｏ－脱乙基酶及苯并芘羟化酶含量显著减少，细胞色素Ｃ还原酶活性降低，但细胞色素Ｐ－４５０、乙基吗啡－Ｎ－脱甲基酶、戊巴比妥侧链羟化酶活性无改变。表明培氟沙星有抑制大鼠肝微粒体酶系中一些酶的活性。     

The effect of galactosamine on rat liver cytochrome P-450 activities

The effect of galactosamine on hepatic drug metabolizing activities was examined in rats. In the microsomal fraction, the contents of cytochrome P-450 (P-450) and cytochrome b5 (b5) and the activity of NADPH-cytochrome c reductase (reductase) were examined for 7 days after galactosamine administration. In addition, substrate metabolizing activities in damaged microsomes were examined using four substrates: aminopyrine, aniline, benzo(a)pyrene (B(a)P) and 7-ethoxycoumarine (7-EC). The contents of P-450 and b5 and the activity of reductase showed a minimal value after 3 days of galactosamine administration and then gradually increased, reaching to the control level after 7 days. All four substrate metabolizing activities showed a similar response as the content of P-450, but the decrement among the four activities was not uniform. The activities of B(a)P hydroxylation and 7-EC deethylation were more impared than those of aminopyrine demethylation and aniline hydroxylation. This nonuniformity was clear on the activity based on P-450. This result suggested that galactosamine disturbed the population of multiple P-450 subtypes, and each P-450 subtype was damaged to the various extent by galactosamine administration.     

Characterization of distinct forms of cytochromes P-450, epoxide metabolizing enzymes and UDP-glucuronosyltransferases in rat skin

Study of drug metabolizing enzyme activity was undertaken in skin microsomal and cytosolic fractions of male and female rats. The presence of several isoforms was revealed from their activities towards selected substrates and from their cross immunoreactivity using antibodies raised against purified hepatic or renal cytochromes P-450, epoxide hydrolase and UDP-glucuronosyltransferases. Cytochrome P-450 content was precisely quantified by second derivative spectrophotometry, 23.1 and 16.5 pmol/mg protein in males and females, respectively. The monooxygenase activity associated to cytochromes P-450IIB1 and P-450IA1 was determined through O-dealkylation of ethoxy-; pentoxy- and benzoxyresorufin. The activity ranged between 4 and 2 nmol/min/mg protein for male and female rats, respectively. These results and Western blot analysis indicated that rat skin microsomes contain both monooxygenase systems associated with cytochromes P-450IIB1 and P-450IA1. By contrast lauric acid hydroxylation, supported by cytochrome P-450IVA1, was not detectable. Activities of epoxide metabolizing enzymes (microsomal and cytosolic epoxide hydrolases; glutathione S-transferase) were also characterized in skin. Microsomes catalysed the hydratation of benzo(a)pyrene-4,5-oxide and cis-stilbene oxide at the same extent, whatever the sex, although the specific activity was 10 times lower than in liver. The hydratation of trans-stilbene oxide by soluble epoxide hydrolase was four times lower than in the liver. Conjugation of cis-stilbene oxide with glutathione in skin and liver proceeded at essentially similar rates, as the specific activity of glutathione S-transferase in skin was only two times less than that measured in hepatic cytosol. Glucuronidation of 1-naphthol, bilirubin but not of testosterone could be followed in the microsomal fraction. Revelation by Western blot indicated that both the isoforms involved in conjugation of phenols and bilirubin were present in skin microsomes. By contrast, the isoform catalysing the conjugation of testosterone was apparently missing. When immunoblotting was carried out using specific antibodies raised against the renal isoforms, the same result was obtained. In addition, an intense staining corresponding to a 57 kD-protein was observed.     

Modulation of rat liver aryl hydrocarbon (benzo[a]pyrene) hydroxylase activity by nutritional effects

Rats malnourished since birth and fed a protein-free diet for 2 wk showed almost undetectable levels of liver microsomal aryl hydrocarbon (benzo[a]pyrene) hydroxylase. Treatment with benzo[a]pyrene rapidly enhanced this activity to levels higher than those observed with untreated normal rats. The carbon-monoxide-reduced cytochrome P-450 spectral peak was shifted from 452 nm in malnourished untreated rats to 448 nm in malnourished benzo[a]pyrene-injected rats and resulted in increases in the intensity of several microsomal protein bands (MW range 46,000-60,000) separated by gel electrophoresis. Malnourished rats then fed with a protein diet exhibited an important increase in aryl hydrocarbon hydroxylase activity, an increase in the intensity of microsomal protein electrophoretic bands (MW range 46,000-60,000), and a shift of the carbon-monoxide-reduced cytochrome P-450 spectral peak from 452 nm to 450 nm. These results suggest that alterations in cytochrome P-450 species related to benzo[a]pyrene metabolism might explain the modulation of this activity by nutritional effects.