Importance of conjugation reactions in determining the qualitative nature of polycyclic aromatic hydrocarbon-DNA interactions.

Polycyclic aromatic hydrocarbons are metabolically activated by microsomal enzymes to reactive metabolites which covalently bind to DNA. The qualitative and quantitative nature of the hydrocarbon-deoxyribonucleoside adducts formed are markedly dependent on the balance of the oxidative and conjugating enzymes present in the activation system. Thus, utilising rat liver microsomes, to metabolically activate benzo(a)pyrene, the major hydrocarbon-deoxyribonucleoside adduct formed is due to metabolic activation of 9-hydroxybenzo(a)pyrene. In striking contrast to this when isolated rat hepatocytes are used to metabolically activate [3H]-benzo(a)pyrene, 9-hydroxybenzo(a)pyrene is conjugated primarily with UDPglucuronic acid and the major hydrocarbon-deoxyribonucleoside adduct formed is due to further metabolism of 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene. Thus the balance and nature of conjugating enzymes present in a tissue will, by determining the nature and amounts of adducts formed, also modulate the biological susceptibility of a particular tissue or cell. In this regard it may be of particular interest that whereas in isolated rat hepatocytes and short-term organ cultures of rodent lung and trachea conjugation with UDPglucuronic acid is quantitatively the major route of conjugation, with short-term organ culture of human lung, sulphate ester conjugation of phenolic substrates appears to be a major route of metabolism. Thus in vivo or in microsome or cell mediated mutagenesis assays of polycyclic aromatic hydrocarbons the susceptibility of a particular cell or tissue will be dependent in part on the relative activities of the oxidative and conjugating enzymes.