This secondary reaction occurs to a trace extent in the bone marrow during normal heme biosynthesis and cell maturation, whereas enhanced ZnPP accumulation appears in circulating erythrocytes during states of iron deficiency in the marrow (15,16).
As a metabolic byproduct that forms during hemoglobin synthesis in the developing erythrocyte, ZnPP is found in blood in healthy individuals at a ratio of ~50 ZnPP molecules per 1 x [10.
The presence of ZnPP in erythrocytes as the result of errant heme synthesis leads to its deposition in the spleen, and possibly the liver, when the aged erythrocytes are sequestered and the heme and ZnPP are released and bound to heme oxygenase (HO) in these organs, leading to the subsequent slower degradation of heme.
Administration of ZnPP to rats leads to its deposition in a variety of organs (plasma, liver, spleen, kidney, lung, and brain), causing decreased HO activity and CO formation (21).
As first described by Maines (18) in 1981, when administered subcutaneously twice daily for 2 consecutive days, 40 nmol/g ZnPP was shown to inhibit by 40-60% hepatic, splenic, and renal HO activity in 5-day-old neonatal rats.
Through measurements of serum BR and hepatic and splenic HO activity, the duration of action of intraperitoneally administered ZnPP (40 nmol/g) to neonatal rats was found to be less than 1 week.
ZnPP and other metalloporphyrin (MP) analogs of heme can play a prominent role in the catabolism of heme by membrane-bound HO in conjunction with cytochrome P450 reductase, NADPH, and [O.
MP analogs of heme, such as the endogenous ZnPP and synthetic derivatives, whose central metal ion and / or 2- and 4-ring substituents have been replaced, are potent competitive HO inhibitors in vitro as well as in vivo (18, 19, 42).
Although measurements of BR in plasma and tissue preparations have been used as the principle indicator of ZnPP function (26, 50), these measurements in whole organisms are considerably more difficult to interpret because BR is distributed into body compartments that are difficult to access (51, 52).
Thus, measurements of CO under controlled and steady-state conditions can be used for the in vitro (61) and ex vivo (62, 63) determination of cellular and tissue HO activity and for the assessment of HO inhibitors such as ZnPP (21).
Many in vitro studies have been performed to elucidate the role of ZnPP in HO-mediated heme degradation (18, 26, 40).
Because these substances are most often formed as an artifact of porphyrin analysis and reflect instead the presence of ZnPP, the conclusions cited are not necessarily invalidated.