Mechanisms of xenobiotic interactions in pneumotoxicity

Brian Jack Day, Purdue University

Abstract

Many xenobiotics require bioactivation by cytochromes P450 to exert their toxicological effects. Induction of P450s forms the basis for many potential interactions where one xenobiotic potentiates the toxicity of another. The lung would appear to be a likely site because it receives 100% of the cardiac output thereby exposing it to systemic compounds and has a vast surface area for exposure to inhaled agents. The aim of this study was to use in vivo damage and in vitro cytochrome P450 markers to probe interaction mechanisms involved in pneumotoxicity. Bromobenzene is a hepatotoxicant and a weak pneumotoxicant. Phenobarbital (an inducer of hepatic P450IIB1 and IIB2) potentiated both hepatic and pulmonary injury produced by bromobenzene as evidenced by dose-dependent increases in serum enzymes and bronchoalveolar lavage fluid cytotoxicity markers. The lack of pulmonary P450IIB1/IIB2 induction by phenobarbital suggests the involvement of hepatic metabolites in mediating bromobenzene-induced pneumotoxicity. Bromobenzene metabolites (bromoquinone-glutathione conjugates) are implicated in renal necrosis through their bioactivation to cysteine conjugates by $\gamma$-glutamyl transpeptidase (GGT). However, inhibition of GGT by acivicin, which has been reported to block renal toxicity, had no effect on bromobenzene-induced pneumotoxicity. To dissociate hepatic from pulmonary P450 metabolism, p-xylene, which induces hepatic but inhibits pulmonary P450, was used as a biochemical tool. p-Xylene potentiated bromobenzene-induced hepatotoxicity without pneumotoxicity. These data suggest that bromobenzene-induced pneumotoxicity in phenobarbital-treated rats involves in part pulmonary bioactivation which is probably P450-mediated. Carbon tetrachloride (CCl$\sb4$) is also a hepatotoxicant and a weak pneumotoxicant. Chronic ethanol treatment has been shown to potentiate CCl$\sb4$-induced hepatotoxicity due to induction of cytochrome P450IIE1. Ethanol is only a weak inducer of pulmonary P450IIE1 and failed to potentiate CCl$\sb4$-induced pneumotoxicity. Pyridine, a better inducer of pulmonary P450IIE1, potentiated CCl$\sb4$-induced pneumotoxicity. These data suggest that the mechanism of CCl$\sb4$-induced pneumotoxicity is similar to that reported in the liver.

Degree

Ph.D.

Advisors

Carlson, Purdue University.

Subject Area

Pharmacology|Toxicology

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