Role of isozyme-specific inhibition of cytochrome P450IIB1 activity in m-xylene-induced alterations in rat pulmonary benzo(a)pyrene metabolism

Stickney, J. A.; Silverman, Diane M.; Schatz, Robert A.

doi:10.3109/00498259109039504

Cited by 12 publications

(12 citation statements)

References 37 publications

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“…This result was also observed in lung following ip administration of the solvent. Unlike the decrease in hepatic AHH activity following ip administration of m-xylene (Stickney et al, 1990), hepatic AHH activity following inhalation was unchanged ( Figure 1A).…”

Section: Resultscontrasting

confidence: 59%

“…The decrease in pulmonary AHH activity correlates with the inhibition of CYP 2B1 activity, the isozyme partially contributing to AHH activity (Nebert et al, 1975). The decrease in CYP 2B1 activity ( Figure 1B) in the lung was also observed after ip injection of m-, o-, or p-xylene (Stickney et al, 1990;Verschoyle et al, 1993) and after p-or o-xylene inhalation Park et al, 1993). CYP 2B1 is responsible for the metabolism of xylenes as well as PAHs, and PAH metabolism by this isozyme is considered a detoxication route (Ioannides & Park, 1987).…”

Section: Discussionmentioning

confidence: 75%

“…Previous experiments with m-xylene [intraperitoneal (ip) injection; 1 g/kg] have resulted in altered cytochrome P-450 (CYP) isozyme activity (Stickney et al, 1990). m-Xylene significantly decreased CYP 2B1 activity in rat lung, while the activity of the isozyme was unaffected in liver.…”

Section: Low-level M-xylen E Inhalation Alters Pulmonary and Hepatic mentioning

confidence: 99%

“…CYP 1A1 substrates include caffeine, steroids, nicotine, and toluene (Tassaneeyakul et al, 1993;Spink et al, 1992;Oguri & Yamada, 1994). The ratio of CYP 2B1 to CYP 1A1 activity is an indirect method for detecting shifts in BaP metabolism toward toxication or detoxication (Stickney et al, 1990;.…”

Section: Low-level M-xylen E Inhalation Alters Pulmonary and Hepatic mentioning

confidence: 99%

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LOW-LEVEL m-XYLENE INHALATION ALTERS PULMONARY AND HEPATIC CYTOCHROME P-450 ACTIVITY IN THE RAT

Foy¹

1996

Journal of Toxicology and Environmental Health

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m-Xylene is a commonly used industrial solvent that has been shown to alter mixed-function oxidase (MFO) activity, in an organ- and isozyme-specific pattern, following intraperitoneal administration of the solvent. The purpose of this work was to determine whether similar alterations occurred in cytochromes P-450 (CYP) following m-xylene inhalation, the primary route of occupational exposure. A single 6-h exposure to m-xylene resulted in the inhibition of aryl hydrocarbon hydroxylase (AHH) activity in the lung while the activity of AHH was unchanged in the liver. CYP 2B1 activity, which is responsible for the metabolism of benzo[a]pyrene (BaP) to relatively nontoxic metabolites, was decreased in lung but not in liver. The activity of CYP 1A1, responsible for the metabolism of BaP to reactive/toxic products, was not altered in lung or liver. The CYP 2B1/1A1 ratio is an indirect indicator of the pattern of BaP toxication/detoxication. This ratio was decreased in lung, suggesting that BaP metabolism is shifted toward toxication. CYP 1A2 and CYP 4B1 activity was decreased in the lung while remaining unchanged in the liver. CYP 2E1 activity was also inhibited in lung while its activity was increased in the liver. This organ-specific inhibition of pulmonary cytochromes P-450 may be due to the lower MFO activity in the lung compared to liver. Alteration of the cytochromes P450 by m-xylene could result in a change in the metabolic profiles of xenobiotics in coexposure or subsequent exposure scenarios in increased or decreased toxicity in an organ-specific fashion.

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Section: Resultscontrasting

confidence: 59%

Section: Discussionmentioning

confidence: 75%

Section: Low-level M-xylen E Inhalation Alters Pulmonary and Hepatic mentioning

confidence: 99%

Section: Low-level M-xylen E Inhalation Alters Pulmonary and Hepatic mentioning

confidence: 99%

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LOW-LEVEL m-XYLENE INHALATION ALTERS PULMONARY AND HEPATIC CYTOCHROME P-450 ACTIVITY IN THE RAT

Foy¹

1996

Journal of Toxicology and Environmental Health

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“…Intraperitoneal o-xylene produced lung-selective inhibition of P-450-related activities similar to those observed for the m-or p-isomer (Pyykko et al, 1987;Park et al, 1994), including decreases in pulmonary P-450 content and AHH, BROD, and EROD activities, as well as a decrease in the BROD/ EROD ratio. This ratio has been used an indirect indicator of the relative contributions of these two P-450 isozymes to xenobiotic metabolism (Stickney et al, 1991;Park et al, 1994;Foy et al, 1996), in particular benzo [a]pyrene (BaP), as BROD and EROD catalyze the formation of detoxication and toxication BaP metabolites, respectively.…”

mentioning

confidence: 99%

EFFECT OF LOW-LEVEL SHORT-TERM o-XYLENE INHALATION ON BENZO[a]PYRENE (BaP) METABOLISM AND BaP-DNA ADDUCT FORMATION IN RAT LIVER AND LUNG MICROSOMES

Park

Schatz²

1999

Journal of Toxicology and Environmental Health, Part A

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o-Xylene is a commonly used solvent that alters mixed-function oxidase (MFO) activity in an organ- and isozyme-specific pattern following intraperitoneal (ip) administration. Similar MFO alterations have been observed after ip or inhalation exposure to other methyl benzenes. These MFO alterations shifted the metabolism of the carcinogen benzo[a]pyrene (BaP) toward formation of toxication metabolites in lung. The purpose of this study was to determine whether o-xylene inhalation caused similar MFO changes and whether these alterations were reflected in altered BaP metabolism and BaP-DNA adduct formation. o-Xylene (300 ppm, 6 h) decreased the activity of arylhydrocarbon hydroxylase (AHH) in lung. CYP2B1 activity (benzyloxyresorufin O-dealkylase; BROD), which is responsible for metabolism of BaP to relatively nontoxic metabolites, was decreased in lung, as was, to a lesser extent, CYP1A1 (ethoxyresorufin O-dealkylase; EROD), which is responsible for metabolism of BaP to reactive/toxic metabolites. The BROD/EROD ratio, an indirect indicator of the pattern of BaP toxication/detoxication, was decreased in lung, suggesting that BaP metabolism is shifted toward toxication. No MFO alterations were observed in liver. In lung microsomes, o-xylene increased formation of 7,8-BaP-diol, while 9,10-BaP-diol, 3-OH BaP, and 9-OH BaP were decreased. In liver, o-xylene increased 9-OH BaP formation, while 4,5- and 9,10-diols as well as total diols were decreased. The toxication/detoxication ratios for BaP individual and total metabolite groups were increased in lung microsomes and unaltered in liver. The major BaP-DNA adduct, BaP diol epoxide-N2-deoxyguanosine, was increased in lung but decreased in liver microsomes from o-xylene-exposed rats. Four minor BaP-DNA adducts were formed in lung and three in liver, only one of which (liver adduct 3) was decreased. The o-xylene-induced increase in BaP adduct formation in lung and decrease in liver indicate that coexposure to organic solvents such as the methyl benzenes may alter the carcinogenesis of BaP, or other PAHs, in an organ-specific fashion.

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Cytochrome P450 destruction and radical scavenging by benzene and its metabolites

Souček

Filipcová

Gut

1994

Biochemical Pharmacology

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Role of isozyme-specific inhibition of cytochrome P450IIB1 activity in m-xylene-induced alterations in rat pulmonary benzo(a)pyrene metabolism

Cited by 12 publications

References 37 publications

LOW-LEVEL m-XYLENE INHALATION ALTERS PULMONARY AND HEPATIC CYTOCHROME P-450 ACTIVITY IN THE RAT

LOW-LEVEL m-XYLENE INHALATION ALTERS PULMONARY AND HEPATIC CYTOCHROME P-450 ACTIVITY IN THE RAT

EFFECT OF LOW-LEVEL SHORT-TERM o-XYLENE INHALATION ON BENZO[a]PYRENE (BaP) METABOLISM AND BaP-DNA ADDUCT FORMATION IN RAT LIVER AND LUNG MICROSOMES

Cytochrome P450 destruction and radical scavenging by benzene and its metabolites

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