Cytochrome C activation A large number of agents cause genetic damage and can induce neoplastic transformation. They include - Chemical carcinogens - Radiant energy - Oncogenic viruses Chemical carcinogens Chemical have long been associated with cancers. Chemical carcinogens are extremely diverse structure. They fall into mainly two categories:- i) Direct acting compounds - They dot not require chemical transformation in the body for their carcinogenicity. ii) Indirect acting compounds -They require metabolic conversion in vivo to produce ultimate carcinogens capable of transforming cells. - Carcinogens can also be inactivated in the body through ceain metabolic pathways. - Thus the carcinogenic potency of a chemical is determined not only by the inherent reactivity of its electrophile derivatives but also by the balance between activation and inactivation reactions. Carcinogenesis is a multistep process: -Initiation During this process a carcinogen (initiator) initiates a cell into carcinogenesis. After a sufficient exposure to the carcinogen, the cell undergoes alteration. All initiating chemical carcinogens are highly reactive electrophiles (have electron deficient atoms) that can react with nucleophiles (electron rich) sites in the cell. Their targets are DNA, RNA and proteins - An initiator cell causes unrepaired alteration in the DNA. - Unrepaired alteration in the DNA is the essential first step in the process of initiation. For the change to be heritable the damged DNA template must be replicated. - Thus for initiation to occur, carcinogen altered cells must undergo at least one cycle of proliferation so that the changes in DNA becomes fixed. Promotion Initiation alone is not sufficient for tumor formation the altered initiator cell has to undergo promotion. Promoters can induce tumors in initiated cells but they are nontumorigenic by themselves. In contrast to the effect of initiators, cellular changes resulting from application of promoters do not affect the DNA directly and are reversible. Fuher more, tumours do not result when the promoting agent is applied before rather than after the initiating agent. The promoters lead to proliferation and clonal expansion of initiated (mutated cells). - When initiator cells proliferate under the influence of promoters they undergo additional mutations developing eventually into a malignant cell. General scheme of events in chemical carcinogenesis Benzopyrine is a polycyclic Aromatic hydrocarbon - Polycyclic aromatic hydrocarbons are one of the most potent carcinogens known. - They are of paicular interest as carcinogens because they are produced in the combustion of tobacco paicularly with cigarette smoking. Benzopyrene is ,found in coaltar, automobile exhaust fumes, smoke from combustion of organic material and in charbroiled. food. It requires metabolic conversion in the body to exe its biological effect like most of the known carcinoma it is metabolized by p450 dependent mono-oxygenase - About 10% of white population has a highly inducible form of one of p450 enzyme (CYPIA1). - This enzyme is induced by Benzopyrene present in cigarette smoke and leads to cancer. First step Cytochrome P450 (cYP 1A1) catalyzes the initial epoxidation. Second step Epoxide hydrolase catalyzes the formation dihydrodiols. Third step Dihydrodiols is fuher metabolized by cytochrome P450 (CYP 1A1) to form vicinal-dioL-epoxide. Fouh step The highly unstable vicinal-diol-epoxide opens spontaneously to .form carhocation. It gives a highly reactive carbonium ion that can form a covalent addition product (i.e., adduct) with cellular macromolecules including DNA and leads to carcinogenesis. Benzopyrene is metabolized bycytochrome p450 and epoxide hydrolase to from ultimate carcinogen -->benzopyrene-7,8 diol 9,10 epoxide-2. Action of polycyclic hydrocarbons on p53. -Benzopyrene activates the human p53 gene through induction of nuclear, factor kappa B activity.