Examination of pulmonary benzene metabolism

Mark William Powley, Purdue University

Abstract

Benzene is an occupational hazard and environmental toxicant. The main concern for humans is acute myelogenous leukemia with limited evidence to suggest lung cancer may result. The toxic effects of benzene are dependent on its metabolism by cytochrome P450. Most physiologically based pharmacokinetic models assume that benzene is metabolized only by CYP2E1 and only in liver. However, the accuracy of these models in predicting metabolism is questionable, especially following inhalation exposure. Two main hypotheses were tested. The first was that cytochrome P450 isozymes other than CYP2E1 are involved in benzene metabolism. The second was that the lung is capable of metabolizing benzene in an in vivo simulation. Studies using specific chemical inhibitors of CYP2E1, CYP2B, and CYP2F in microsomal preparations indicate that CYP2E1 is the P450 isozyme primarily responsible for benzene metabolism to phenol, hydroquinone, and catechol in the livers of mice, rats, and humans. CYP2F plays an important role in pulmonary benzene metabolism in all species examined, while CYP2E1 is of slightly lesser importance. These conclusions were confirmed by the finding of very low metabolic activity in CYP2E1 knockout mice compared to wild-type mice. This study also showed that while CYP2E1 is the most important cytochrome P450 isozyme in the liver, it was only responsible for ∼50% of pulmonary benzene metabolism. In the metabolism of phenol, a benzene metabolite, the use of specific chemical inhibitors showed that CYP2E1 is responsible for ∼50% of hepatic and pulmonary metabolism. The remaining hepatic activity is not due to the action of CYP2F2 or CYP2B. However, CYP2F2 is important in pulmonary metabolism of phenol. The use of CYP2E1 knockout and wild-type mice show that CYP2E1 is not the only cytochrome P450 isozyme involved in phenol metabolism by hepatic or pulmonary microsomes. These results are consistent with the results of the specific chemical inhibitor study. Further evidence of the lung's importance in benzene metabolism was demonstrated in isolated perfused rodent lung experiments. Benzene was metabolized in rats during exposure via the pulmonary vasculature and mice during both exposure via the pulmonary vasculature and inhalation.

Degree

Ph.D.

Advisors

Carlson, Purdue University.

Subject Area

Toxicology|Anatomy & physiology|Animals

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