Thirty-three porphyrins or metalloporphyrins corresponding to the general formula [meso-[N-methyl-4(or 3 or 2)-pyridiniumyl]n(aryl)4-nporphyrin]M (M = H2, CuII, or ClFeIII), with n = 2-4, have been synthesized and characterized by UV-visible and 1H NMR spectroscopy and mass spectrometry. These porphyrins differ not only in the number (2-4) and position of their cationic charges but also in the steric requirements to reach even temporarily a completely planar geometry. In particular, they contain 0, 1, 2, 3, or 4 meso-aryl substituents not able to rotate. Interaction of these porphyrins or metalloporphyrins with calf thymus DNA has been studied and their apparent affinity binding constants have been determined by use of a competition method with ethidium bromide which was applicable not only for all the free base porphyrins but also for their copper(II) or iron(III) complexes. Whatever their mode of binding may be, their apparent affinity binding constants were relatively high (Kapp between 1.2 x 10(7) and 5 x 10(4) M-1 under our conditions), and a linear decrease of log Kapp with the number of porphyrin charges was observed. Studies of porphyrin-DNA interactions by UV and fluorescence spectroscopy, viscosimetry, and fluorescence energy transfer experiments showed that not only the tetracationic meso-tetrakis[N-methyl-4(or 3)-pyridiniumyl]porphyrins, which both involved four freely rotating meso-aryl groups, but also the corresponding tri- and dicationic porphyrins were able to intercalate into calf thymus DNA. Moreover, the cis dicationic meso-bis(N-methyl-2-pyridiniumyl)diphenylporphyrin, which involved only two freely rotating meso-aryl groups in a cis position, was also able to intercalate. The other meso-(N-methyl-2-pyridiniumyl)n(phenyl)4-nporphyrins, which involved either zero, one, or two trans freely rotating meso-aryl groups, could not intercalate into DNA. These results show that only half of the porphyrin ring is necessary for intercalation to occur.

Inhibition of soybean lipoxygenase (L-1) and potato 5-lipoxygenase (5-PLO) by the pyrazoline derivatives phenidone and BW755C only occurs after oxidation of these compounds by the peroxidase-like activity of the lipoxygenases. There is a clear relationship between this oxidation and the irreversible inactivation of L-1. The final product of phenidone oxidation by L-1, 4,5-didehydrophenidone, is not responsible of this inactivation, but the species derived from a one-electron oxidation of phenidone plays a key role in L-1 inactivation. In the absence of O2, inactivation of 1 mol of L-1 occurs after the oxidation of 34 mol of phenidone and the covalent binding of 0.8 mol of phenidone-derived metabolite(s) to L-1. In the presence of O2, inactivation of 1 mol of L-1 occurs already after oxidation of 11 mol of phenidone and only involves the covalent binding of 0.4 mol of phenidone-derived metabolite(s) to L-1. A mechanism is proposed for L-1 inactivation by phenidone, which involves the irreversible binding of a phenidone metabolite to the protein and the oxidation of an L-1 amino acid residue (in the presence of O2).

Monooxygenases are widely distributed enzymes which catalyze dioxygen activation using two electrons and two protons, with the insertion of one oxygen atom from O2 into a substrate and the formation of water (Eqn 1).A great number of these monooxygenases contain a heme protein called cytochrome P-450 which is the site of dioxygen activation. These cytochrome-P-450-dependent monooxygenases are involved in many steps of the biosynthesis and biodegradation of endogenous compounds such as steroids, fatty acids, prostaglandins and leukotrienes. They also play a key role in the oxidative metabolism of exogenous compounds such as drugs and other environmental products allowing their elimination from living organisms. Because of their wide distribution in living organisms and their very important role in biochemistry, pharmacology and toxicology, cytochromes P-450 have been the subject of many studies during the last 20 years. Thus, much is known about the structure and function of cytochromes P-450 (for recent reviews, see [l -41) and more than 60 cytochromes P-450 from various origins have been sequenced [5].However, because of the high molecular mass of cytochromes P-450 (about 50 kDa), it is still difficult to determine the detailed mechanism of substrate oxidations and the nature of the iron intermediates involved in these processes. In particular, it is difficult to determine the molecular structure of the iron-metabolite complexes formed from time to time during the metabolism of some classes of substrates. A possible way to solve these problems is to use biomimetic chemical systems involving iron-porphyrins.In fact, iron-porphyrin model systems for cytochromes P-450 may be used for three main purposes. The first is to determine the nature of the iron complexes involved as intermediates in the catalytic cycle of dioxygen activation and substrate hydroxylation by cytochrome P-450. Model ironporphyrin complexes for all these intermediates except one have been prepared and completely characterized by various spectroscopic techniques. Their structures have been established by X-ray analysis. The spectroscopic characteristics of these model complexes have been found to be very similar to Ahhreviutions. TMP, tetramesitylporphyrin; TPP, meso-tetraphenylporphyriu; TDCPP, tetra-2,6-dichlorophenylporphyrin.those of the corresponding enzymatic complexes and the use of these models has largely contributed to our present detailed knowledge of the catalytic cycle of cytochrome P-450. This first interest of the use of models has been described in previous reviews (see for instance [6 -91) and will not be treated in this article.A second objective of the use of chemical models for cytochromes P-450 is to understand as much as possible about the mechanisms of cytochrome P-450 during these reactions. In particular, the preparation and complete characterization of models for the cytochrome-P-450 -iron -metabolite complexes formed during the metabolism of some drugs or exogenous compounds should allow us to determine the chemical fu...