Microsomal hydroxylation

Dexamethasone, the macrolide antibiotic triacetylo-leandromycin, and phenobarbital are all well established inducers of the CYP3A subfamily, and can increase microsomal 4-hydroxylation of RA in rat liver. To what extent this is also the case for humans is not completely clear. 

In rats and mice, TBT compounds are hydroxylated by microsomal monooxygenase attack (see Environmental Health Criteria 116). Hydroxylation can occur on either the alpha or beta carbon of the butyl group, that is, alpha or beta in relation to the Sn atom (see Figure 8.5). After hydroxylation, the hydroxylated moiety breaks away to leave behind dibutyltin. 

Smith RV, Erhardt PW, Leslie SW. Microsomal O-demethylation, A-demethyl-ation and aromatic hydroxylation in the presence of bisulfite and dithiothreitol. Res Commun Chem Path Pharmacol 1975 12 181-4. 

Compound NPYR Species Rat Tissue Preparation Liver microsomes Comments identification of 4-hydroxybutyr-aldehyde (as its 2,4-dinitrophenyl-hydrazone) from a-hydroxylation Reference 9... 

NPYR Rat Liver microsomes HPLC assay for a-hydroxylation 15... 

NPYR Syrian golden hamster Liver microsomes enhanced a-hydroxylation and mutagenicity in ethanol-consuming hamsters 10... 

NPYR Rat Liver and lung microsomes and postmitochondrial supernatant a-hydroxylation but not p-hydroxy-lation in both tissues 13... 

NNN Rat Liver microsomes assay for a-hydroxylation and the effect of a-deuterium substitution 33... 

NNN Rat Liver microsomes identification of products of p-hydroxylation and pyridine-N-oxidation 36... 

NPIP Rat Liver microsomes identification of 5-hydroxypenta-nal from a-hydroxylation 46... 

The metabolism of NNN in the F-344 rat is summarized in Figure 2. Liver microsomal a-hydroxylation of NNN leads to 2 -hydroxyNNN [ ] and 5 -hydroxyNNN [M. These unstable... 

The effects of deuterium substitution on the rates of a-hydroxylation of NNN have been measured. The results obtained in vitro, with rat liver microsomes, showed only a small deuterium isotope effect of 1.2 for 2 -hydroxylation, whereas a significant effect of 2.4-2.7 was observed for 5 -hydroxylation (33). Analogous results were obtained 2n vivo when the urinary metabolites... 

Only limited metabolic studies have been carried out on NPIP. It undergoes a-hydroxylation by rat liver microsomes to give 5-hydroxypentanal, a process analogous to the formation of... 

Analysis of the products formed from NHEX in vitro using rat liver microsomes and postmitochondrial supernatant resulted in the identification of 3-hydroxyNHEX from p-hydroxylation and 4-hydroxyNHEX from y-hydroxylation. The ratio of 4-hydroxyNHEX to 3-hydroxyNHEX was 3 to 1. Both conformeric forms of each of these metabolites were detected (53). From ix vitro data which are available so far for NPYR, NNN, NPIP, and NHEX, it does appear that the rates of a- and y-hydroxylation (when possible), exceed those of p-hydroxylation. 

The metabolism of NMOR in the rat is outlined in Figure 4. o-Hydroxylation yields the unstable intermediates and the latter hydrolyzes to (2-hydroxyethoxy)acetaldehyde [7] which has been identified as a liver microsomal metabolite by isolation of the corresponding 2,4-dinitrophenylhydrazone (59). (2-Hydroxy-ethoxy)acetaldehyde, which exists predominantly as the cyclic hemiacetal was not detected in the urine of rats gavaged with 125 mg/kg NMOR. However, (2-hydroxyethoxy)acetic acid was a major urinary metabolite (16% of the dose). These transformations are analogous to those observed with NPYR and NNN. 

Dady JM, SP Bradbury, AD Hoffman, MM Voit, DL Olson (1991) Hepatic microsomal Al-hydroxylation of aniline and 4-chloroaniline by rainbow trout (Oncorhyncus mykiss). Xenobiotica 21 1605-1620. 

Cederbaum, A.I. (1987). Microsomal generation of hydroxyl radicals its role in microsomal ethanol oxidising system (MEOS) activity and requirement for iron. Ann. N. York Acad. Sci. 492, 35-49. 

Klein, S.M., Cohen, G., Lieber, C.S. and Cederbaum, A.l. (1983). Increased microsomal oxidation of hydroxyl scavenging agents and ethanol after chronic consumption of ethanol. Arch. Biochem. Biophys. 223, 425-432. 

Bolton, J. L. Thompson, J. A. Oxidation of butylated hydroxytoluene to toxic metabolites factors influencing hydroxylation and quinone methide formation by hepatic and pulmonary microsomes. Drug Melah. Dispos. 1991, 19,467-472. 

MgCl2 (10 mM) increased the apparent Km (83 to 173 /am) and reduced the Vjnax (3.4 to 2.4 min-1) of triazolam 4-hydroxylation by expressed CYP3A4 [21]. However, both MgCl2 (30 mM) and CaCl2 (30 mM) significantly increased reaction rates of testosterone 6/3-hydroxylation (approximately threefold) and nifedipine oxidation (three- to six-fold) by human liver microsomes (HLMs) or recombinant CYP3A4 (reconstituted with b5 and GSH) [15]. It was suggested that divalent cation stimulation on the activity was related to involvement of b5 in CYP 3A4 reaction. 

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