Toxicological and endocrinological aspects of cytochrome P450 in breast and lung

Cytochrome P450 (CYP) enzymes have well characterized functions in dispositionand pharmacokinetics of xenobiotics as well as in biosynthesis and/or metabolismof endogenous compounds, such as steroid hormones, bile acids, arachidonic acid andits derivatives. Cytochrome P450 mediated metabolic activation is known to be a prerequisitefor the cytotoxic and mutagenic activity of many environmental toxins and procarcinogens.Xenobiotic and steroid-metabolizing P450 enzymes are found in many tissues in thebody, although at lower levels than in the liver and adrenal glands. It is the majorhypothesis of this thesis that cell-specific expression of P450 can influence hormonemetabolism and xenobiotic toxicity in target cells. In order to test this theorywe have investigated P450 mediated activation of procarcinogens in the lung and characterizedthe P450 content of rat and human breast. Environmental factors have been implicated in the etiology of both lung and breastcancer. Heterocyclic amines are a group of dietary procarcinogens, that produce tumorsat multiple sites in experimental animals and that have been proposed to play a rolein human cancer. The capacity of rat and mouse lung microsomes to activate the heterocyclicamines IQ, MelQx and PhlP was demonstrated using the Ames mutagenicity test. Withinhibitory antibodies it was shown that CYP2A3 mediated a large part of the activationof IQ in rat lung microsomes. CYP2A3 has been detected in rat lung and nasal mucosa,but not in the liver and thus these studies underscore the importance of studyingextrahepatic reactions. The mammary gland is characterized by its hormonal regulation of growth and differentiation.In studies on rat breast, we could show that the P450 profile also varies with ageand endocrine status of the animals. Quantitation of enzyme levels was achieved afterpartial purification of P450 and expression of P450 enzymes was analysed by Westernblot of the protein in combination with RT PCR of mRNA. The studied P450