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

Abstract

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.

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

“…Blood levels of o-xylene were in the same range (0.7-2.3 µmol/g) as those observed after similar (300 ppm, 6 h) inhalation exposures to m-or p-xylene Foy et al, 1996).…”

“…Intraperitoneal (ip) administration or inhalation of xylene and xylene isomers decrease rat pulmonary cytochrome P-450 content and related enzyme activities such as ethoxyresorufin O-dealkylase (EROD; CYP1A1) activity, benzyloxyresorufin O-dealkylase (BROD; CYP2B1) AHH activity, and n-hexane hydroxylation activity (Toftgard & Nielsen, 1982;Elovaara et al, 1987;Pyykko et al, 1987;Foy et al, 1996), while increasing liver microsomal P-450 content and MFO-related enzymatic activities (Elovaara et al, 1980;Savaolainen et al, 1978;Toftgard et al, 1981). Of the three isomers, o-xylene has been the least studied, likely because it is a lesser component of xylene mixtures and is less utilized in industry.…”

“…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.…”

Induction of Cytochromes P-450 1A1 and 1B1 by Motorcycle Exhaust Particulate In Human Breast Cancer MCF-7 Cells

“…Previous studies have demonstrated a marked selectively in the effects of endo-and xenobiotics on monooxygenase activities. For instance, inhalation exposure of rats to m-xylene produced selective increases of hepatic methoxyresourfin O-dealkylase and N-nitrosodimethylamine demethylase activities without affecting other monooxygenase activities toward the substrates benzo[a]pyrene, benzyloxyresorufin, 7-ethoxyresorufin, and 2-aminofluorene (Foy et al, 1996). The nature of the possible E2 modulation of xenobiotic metabolism requires further investigation .…”

“…Cytochromes P-450 1A1 and 1B1 are involved in metabolic activation of carcinogenic PAH and hydroxylation of mammary carcinogen 17b -estradiol (E2) (Spink et al, 1992;Hayes et al, 1996;. These carcinogen-and estrogen-metabolizing cytochromes P-450 1A1 and 1B1 are expressed in many tissues, including liver, kidney, lung, and mammary glands (Sutter et al, 1994;Foy et al, 1996). Cytochromes P-450 1A1 and 1B1 are responsive to the modulatory effects of xenobiotics.…”