Diminished drug metabolism due to hormonal effects of cobalt mesoporphyrin on flavoproteins.
Substituted metalloporphyrins, in addition to their use as pharmacological agents, are used to investigate metabolic pathways by inhibiting cytochrome P-450. We have examined the specificity of this approach with cobalt mesoporphyrin (CoMP). In vivo, CoMP (50 mumol/kg, s.c.) decreased rat hepatic microsomal cytochrome P-450, NADPH cytochrome P-450 reductase, benzphetamine N-demethylase (BZPH) activity, and thyroid hormones by > 50%, all of which returned to control levels after 45 days; testosterone levels were also reduced at this dose. The half-life of CoMP was 18 days, which is consistent with this sustained effect. At 10 mumol/kg of CoMP, the reductase activity was decreased, but cytochrome P-450 was unchanged. An effect of residual CoMP on the reductase was ruled out as the CoMP content of tissue fractions was not high enough to inhibit directly the reductase activity (even after 50 mumol CoMP/kg). However, immunoblots indicated a lower level of immunoreactive reductase protein following treatment. After 8 weekly doses of 1 mumol CoMP/kg, BZPH activity was 39% less than control but neither P-450 content nor reductase activity was significantly changed. The P-450 content and reductase activity in rabbits were much less affected by CoMP, perhaps due to differences in the disposition of CoMP. Thyroidectomy decreased reductase activity in rats to an extent that was seen with CoMP at 50 mumol/kg; CoMP treatment of thyroidectomised rats did not further decrease reductase activity. Supplementation with thyroid hormone blocked the CoMP-related decrease. The flavin-containing monooxygenase was decreased by CoMP and by castration, and the decrease was not blocked by the thyroid hormone supplement. Thus in the rat, the CoMP-related decreases in thyroid hormone and testosterone decrease flavoproteins that support or mediate monooxygenase activities. This is contrary to the reported specificity of this class of compound as inhibitors of cytochrome P-450.
Yanni
S B
SB
Department of Drug Metabolism, Glaxo Research Institute, Glaxo Inc., Research Triangle Park, NC 27709.
Chism
J P
JP
Rickert
D E
DE
Serabjit-Singh
C J
CJ
D000818:Animals; D003037:Cobalt Radioisotopes; D065607:Cytochrome P-450 Enzyme Inhibitors; D004334:Drug Administration Schedule; D005420:Flavoproteins / Q000187:drug effects*; D015151:Immunoblotting; D008297:Male; D008652:Mesoporphyrins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009251:NADPH-Ferrihemoprotein Reductase / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism*; D014018:Tissue Distribution
D003037:Cobalt Radioisotopes; D065607:Cytochrome P-450 Enzyme Inhibitors; D005420:Flavoproteins; D008652:Mesoporphyrins; D013963:Thyroid Hormones; C084061:cobalt mesoporphyrin; D013739:Testosterone; D009251:NADPH-Ferrihemoprotein Reductase