No abstract

In contrast to several authors who found hepatic cytochrome P 450 2D6 (CYP2D6) metabolising status to be clinically unimportant in treatment with the CYP2D6 substrate, risperidone, we report on a 17-year-old schizophrenic patient who suffered from severe extrapyramidal side effects (EPS) while being treated with risperidone at 4 mg per day. He was genotyped as a CYP2D6 poor metaboliser (PM). The active moiety of risperidone (sum of risperidone and 9-hydroxyrisperidone) was elevated and increased even further under co-medication with haloperidol and biperiden. We conclude that the PM phenotype for CYP2D6 of this patient had major clinical importance in treatment with risperidone. Most likely metabolic pathways other than CYP2D6 were also involved that are probably inhibited by haloperidol.

The application of magnetic circular dichroism as an optical probe for simultaneous identification and determination of at least two microsomal cytochromes is demonstrated. The assignments of the bands in the spectra of microsomal suspensions are made from the spectra of soluble preparations of cytochrome P-450 obtained from Pseudomonasputida and of cytochrome b5 obtained from rat livers.Many nonpolar compounds, both endogenous and foreign, are hydroxylated in mammalian tissues with the resultant formation of water-soluble metabolites. In 1958 Klingenberg (1) and Garfinkel (2) independently demonstrated the presence of a carbon monoxide-binding heme protein in rat liver microsomes. Since that time a considerable body of evidence has implicated this pigment, now commonly referred to as cytochrome P-450 (P-450), as a central constituent of enzyme systems responsible for many biological hydroxylation reactions in mammals, insects, and micro-organisms. Notwithstanding the vast amount of effort that has been expended during the last two decades, many questions remain as to the mechanism of biological oxidations involving P-450. Much of the literature concerning research in this field is covered in several recent review articles (3-6) and symposium compendia (7,8).Optical spectrophotometry (9) has been the most widely used physical method in the investigation of microsomal mixed function oxidase systems. Unfortunately, this application of optical spectrophotometry is not straightforward. The main difficulty stems from the physical association of P450 with the phospholipids of the microsomal membrane. Direct measurement of optical spectra of hemoproteins in microsomal preparations does not, therefore, lead to highly meaningful results because of the light scattering caused by the turbidity of such suspensions. Interpretation of optical spectra is further hindered by the presence of a second microsomal hemoprotein, cytochrome b5 (b5), as well as by the occurrence of cytochrome P-420 (P420), a denatured form of P450. In order to surmount these difficulties, recourse is frequently made to difference spectroscopy (9).Abbreviations: MCD, magnetic circular dichroism; P450, microsomal cytochrome P-450; P-450ca0, cytochrome P-450 from camphor-grown Pseudomonas putida; b5, cytochrome b5; P-420, cytochrome P420. * For part XXIV, see Eckstein, H., Barth, G., Linder, R. E., I Author to whom correspondence should be addressed.We now present the results of our preliminary investigation of the application of magnetic circular dichroism spectroscopy (MCD) to the determination of microsomal and bacterial cytochromes. MCD and magneto-optical rotatory dispersion (MORD) (10) have found previous appiication in the study of hemoproteins such as hemoglobin and myoglobin (11-15) and cytochromes c (12, 16, 17), b2 (18, 19), and b5 (19). The present study, however, is the first application of MCD to microsomal cytochromes. We show that bands observed in the MCD spectra of microsomal suspensions can be directly correlated with the bands ...

No abstract

No abstract